Amorphous Drug Delivery Systems: Molecular ...

Critical Reviews™ in Therapeutic Drug Carrier Systems, 21(3):133–193 (2004)

Amorphous Drug Delivery Systems: Molecular Aspects, Design, and Performance Aditya Mohan Kaushal, Piyush Gupta, & Arvind Kumar Bansal Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India Address all correspondence to Arvind Kumar Bansal, Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, 160 062, India; [email protected] Referees: Dr. Manish K. Gupta, GlaxoSmithKline, NCE Development, Fıve Moore Drive, PO Box 13398, Research Triangle Park, NC 27709; Dr. Rodolfo Pinal, Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907

ABSTRACT: The biopharmaceutical properties—especially the solubility and permeability—of a molecule contribute to its overall therapeutic efficacy. The newer tools of drug discovery have caused a shift in the properties of drug-like compounds, resulting in drugs with poor aqueous solubility and permeability, which offer delivery challenges, thus requiring considerable pharmaceutical manning. The modulation of solubility is a more viable option for enhancing bioavailability than permeability, because of the lack of “safe” approaches to enhance the latter. Solid-state manipulation in general, and amorphization in particular, are preferred ways of enhancing solubility and optimizing delivery of poorly soluble drugs. This review attempts to address the diverse issues pertaining to amorphous drug delivery systems. We discuss the various thermodynamic phenomenon such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular-level chemical interactions that contribute to the ease of formation, the solubility advantage, and the stability of amorphous drugs. The engineering of pharmaceutical alloys by solubilizing and stabilizing carriers, commonly termed solid dispersions, provide avenues for exploiting the benefits of amorphous systems. Carrier properties, mechanisms of drug release, and study of release kinetics help to improve the predictability of performance. The review also addresses the various barriers in the design of amorphous delivery systems, use of amorphous form in controlled release delivery systems, and their in vivo performance. KEYWORDS: glass, thermodynamics, stability, solubility, bioavailability, solid dispersion

0743-4863/04$5.00 © 2004 by Begell House, Inc., www.begellhouse.com

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A. M. KAUSHAL ET AL.

I. INTRODUCTION The biopharmaceutical properties of a molecule contribute critically to its “drugability.” More than 40% of new candidates entering drug development pipeline fail because of non-optimal biopharmaceutical properties.¹ These properties have a significant influence on the drug’s absorption, distribution, metabolism, excretion, and toxicity. Over the years, tools of drug discovery have caused a perceptible shift in biopharmaceutical properties. Pharmaceutical companies have been primarily employing two strategies: rational drug design (RDD) and high throughput screening (HTS) for drug discovery.² In either case, lead compounds are identified based on screening in an environment that is remotely related to the biological system. The molecule/receptor interaction is studied, bypassing all the barriers normally encountered during its delivery. Analysis of the properties of numerous drug-like compounds has revealed an interesting trend over a period of time. RDD has lead to compounds with (1) higher molecular weight, (2) increased H-bond acceptors, but (3) unchanged lipophilicity, and consequently poorer permeability. On the other side, HTS has led to compounds with (1) higher molecular weight, (2) increased lipophilicity, but (3) unchanged H-bond acceptors, and consequently, poorer solubility characteristics. These changes in biopharmaceutical properties have caused delivery problems and are a main reason for pharmaceutical manning in early drug discovery and exploratory development phase.²,³ Various attempts have been made to identify chemical markers that correlate well to the bioavailability (BA) of designed molecules.⁴-⁷ These differ in certain aspects but tend to converge on highlighting the importance of molecular weight and lipophilicity in influencing the aqueous solubility and, hence, the oral BA of drugs. Drug activity depends on the triad of potency (dose), solubility, and permeability.⁵,⁸ Potency is an intrinsic property of the molecule, while solubility and permeability are the most important biopharmaceutical properties determinant of a drug’s BA. The biopharmaceutics classification system (BCS) is also based on these two properties and divides drugs into four classes: Class I (high solubility and permeability); Class II (low solubility and high permeability); Class III (high solubility and low permeability); and Class IV (low solubility and permeability).⁹ Recently, a quantitative BCS has highlighted the importance of transit flow, in addition to solubility and permeability, on the drug absorption process.¹⁰ The BCS defines three dimensionless numbers—dose number (Do), dissolution number (Dn), and absorption number (An)—to characterize drug substances.¹¹ These numbers are a combination of physicochemical properties of the drug and physiological parameters. The Do attaches a physiological relevance to dose by considering the volume of fluid required to dissolve the total dose. Drugs with Do < 1 are classified as highly soluble, whereas those with Do > 1 are termed poorly soluble. In a recent attempt to categorize WHO essential drugs based on BCS, 27.7% of drugs were

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AMORPHOUS DRUG DELIVERY SYSTEMS

reported to be poorly soluble.¹² The BCS has not only transformed the way scientists today approach drug delivery, but it has also revolutionized the development of new drug molecules. The modulation of solubility and permeability of a drug molecule for optimizing its delivery uses diverse approaches. The alteration of permeability has involved use of (1) metabolism inhibitors,¹³ (2) ion-pairing and complexing agents,¹⁴ (3) lipid and surfactant adjuvants,¹⁵ and (4) inhibitors of secretory proteins.¹⁶ However, cumulative experience has shown that these approaches are limited in their application, because of acute or chronic toxicity concerns resulting from their capacity to alter the physiology of the body. On the other hand, aqueous solubility can be managed more effectively by physical modification of the drug.¹⁷ Curatolo¹⁸ has reported that the transintestinal absorption rate constant (Ka) for different drugs varies over only ~50 fold range (0.001–0.050 min–¹), whereas drug solubility can vary over six orders of magnitude (0.1 mcg/mL–100.0 mg/mL). Hence, achievable permeability enhancement for a given drug versus the apparent solubility improvement by formulation approaches would follow the same order. Even in the drug discovery setting, it is often productive to prepare analogs with increased solubility, even if permeability is further compromised.¹⁸ This is because poor solubility is likely to result in absorption problems, because the flux of drug across the intestinal membrane is proportional to its concentration gradient between intestinal lumen and the blood. This is likely to be the case even with a highly permeable compound. Conversely, a compound with high solubility might be well absorbed even if it possesses a moderate to low permeation rate.⁸,¹⁹ An example of the latter case is azithromycin, which, in spite of having a very low permeability (Ka = 0.001 min–¹), is well absorbed because of its high solubility (50 mg/mL). Quantitative models describing the drug absorption process include the mixing-tank model,²⁰ the absorption potential model,²¹ and the concept of maximum absorbable dose (MAD).²² The first two models consider solubility, initial particle size, surface area, concentration gradient, and dose in predicting drug absorption, while MAD is a simplified concept that represents the quantity of drug that could be absorbed if the small intestine is saturated with drug for the average transit time. MAD = S .K a .SIWV .SITT

(1)

where S is the solubility at pH 6.5; SIWV is the small intestinal water volume; and SITT is the small intestinal transit time. It is apparent from Equation 1 that an increase in drug solubility will result in increased MAD and in certain cases can even compensate for dismally low permeability. This highlights the modulation of solubility as a more attractive proposition than permeability for improving the delivery of drugs.

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II. DRUG AQUEOUS SOLUBILITY II.A. Contributors to Aqueous Solubility The aqueous solubility of a molecule is a complex interplay of several factors, ranging from the H-bond donor and acceptor properties of the molecule and of water, to the energetic cost of disrupting the crystal lattice of the solid in order to bring it into solution.²³,²⁴ The simultaneous roles of factors make it impossible to calculate the outcome by simple summation of the contributing factors. However, in simplified terms, the solubility of a given solid solute can be modeled as⁵:

S = f (crystal packing energy + cavitation energy + solvation energy)

(2)

The cavitation energy is the energy required (endothermic) to create a cavity within water by breaking its H-bonds. The solvation energy is the energy released (exothermic) as a result of favorable interaction between drug and water molecules. These two terms can be predicted based upon the contributions of the functional groups of the molecule. According to the general model for solute-solvent interactions,²⁵ all solution phase processes (the last two terms in Equation 2) can be modeled in terms of one or more gas-to-solution transfer processes. The free energy of each gas-to-solution transfer, in turn, is the sum of free energy of cavity formation and free energy of solute/solvent interaction. The crystal packing energy (CPE) is the energy necessary to disrupt the crystal lattice and make the drug molecule participate in the solubilization process. Depending on different lattice orders (solid-state forms), the energy required for a molecule to “escape” from the lattice to participate in the solubilization process may vary.²⁶ It is difficult to model CPE, although attempts have been made based upon the concept of minimization of crystal energy.²⁷

II.B. Solubilization Approaches Various techniques are employed to increase the drug solubility, such as prodrug approach; salt formation; complexation (inclusion complexes); use of cosolvents, emulsions, and microemulsions; use of surface active agents; and solid-state manipulation. The chemical modification of a parent molecule to form soluble prodrug requires the drug molecule to possess functional group(s) capable of derivatization by reacting with a promoiety. However, the alteration of chemical structure can affect many other properties, including toxicological profile.²⁸ Salt formation is applicable only

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to ionic drugs, which excludes the use of this strategy for neutral drug molecules.²⁹ From the regulatory perspective, the approval of prodrugs and salts is a tedious task, disfavoring their general applicability.³⁰ Therefore, these solubility enhancement approaches are usually explored during drug discovery or early development phases only. Surfactants³¹,³² improve solubility by promoting wetting and causing micellar solubilization. However, their possible interaction with drugs, the effect of pH on their performance, and their capacity to alter physiological processes are causes of concern. The use of complexing agents, including formation of inclusion complexes with cyclodextrins, is plagued by problems of its concentration-dependent toxicity and reversibility of complex, which prevents their widespread use.³³ Cosolvents, emulsions, and micro-emulsions, although useful for formulation of liquid products, cannot be used in solid dosage forms. Solid-state manipulation is one of the preferred ways to enhance solubility for optimizing delivery of insoluble drugs. Solid-state is divided into three levels: molecular, particle, and bulk level.³⁴,³⁵ Particle size reduction, the first-line strategy for improving drug dissolution rate, works by increasing the surface area per unit mass. The relative increase in activity (solubility) on size reduction of a crystal is modeled by the classic Gibbs–Kelvin equation, which, when adapted to the solubility of solids, is known as the Ostwald–Freundlich equation³⁶: ⎛ a − ∆( ∆G ) = ln ⎜ ⎝ a0

⎞ 2.γ.υ ⎟= ⎠ R.T .r

(3)

where ∆(∆G) is the difference in the free energy of a solution of small and large particles, a/a0 is the ratio of activity increase on decreasing a large crystal to a radius r, γ is the average surface free energy of crystal, ν is the molar volume of solute, R is the universal gas constant, and T is the absolute temperature. It is necessary for particles to be in the submicron range to elicit a dramatic change in solubility. Nanosuspensions and “particulate” microcrystalline solid dispersions are attempts to further lower the particle size.³⁷ However, accompanying poor flow properties, generation of static charges, and agglomeration can limit the advantages of these approaches. Generation of different crystalline (polymorph, pseudo-polymorph, cocrystal) or amorphous forms, the changes at molecular level, offers another promising way to enhance drug dissolution rate and apparent solubility,³⁸,³⁹ thus affecting its “developability.”⁴⁰ The crystalline form is characterized by structural units, termed unit cells, that are repeated regularly in three-dimensional space.⁴¹ On the other hand, an amorphous solid is characterized by a short-range molecular order and lack of a well-defined molecular conformation.⁴² These forms can have different properties

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such as stability, mechanical behavior, and solubility that can be exploited beneficially by formulation scientists. Amorphous materials are also termed glass⁴³ (window glass being the best known example of amorphous solid), disordered systems⁴⁴ (due to randomness in molecular conformation), and frustrated systems⁴⁵ (due to geometric and symmetry frustration at molecular level).

II.C. Amorphous Versus Crystalline Forms Of the three forms, amorphous, polymorphic, or pseudo-polymorphic, as a tool for improving solubility, the amorphous form is often the first choice because of its several advantages.¹⁹ Fırst, the solubility differences between amorphous and crystalline forms of a drug are significantly greater than those between different crystalline polymorphs.⁴⁶ Second, the stabilization of metastable polymorph is a challenge, because by definition, any polymorph would involve only drug/drug interaction, and a drug/stabilizer interaction would destroy its identity. The amorphous form, although unstable because of higher free energy, can be stabilized by molecular interaction between drug and stabilizer without affecting the existence of the amorphous form.³⁹

III. AMORPHOUS STATE Once the domain of ceramists and polymer scientists, the glasses are now being used by scientists in various other fields.⁴⁷ The transformation between supercooled liquid and the glassy state is a broadly occurring phenomenon that has applicability in areas as diverse as material sciences and biology. Glass formation or vitrification is the manner in which nature protects organisms against harsh environmental conditions (say, in desert or arctic regions),⁴⁸ the strategy mankind uses for preservation of food stuffs,⁴⁹ and the way highly pure semiconductors and optics are prepared.⁵⁰ It is also the form in which most water is present in the universe.⁵¹ For pharmaceuticals, there is a renewed interest in the amorphous state because of its distinct properties, which provides attractive avenues for the delivery of insoluble drugs. In particular, the solubility advantage offered by these systems is of considerable interest, although certain limitations, such as their physical instability, have prevented their extensive commercialization. Thereby, it becomes important to understand the molecular and thermodynamic properties that contribute to the solubility and stability of amorphous drugs. The properties include glass transition temperature, fragility, molecular mobility, devitrification kinetics, and molecularlevel chemical interactions.

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III.A. Formation of Amorphous State Cooling from melt is the most commonly employed technique for glass formation and is also the most deeply studied. At temperatures well above the melting point (Tm), molecules are highly disordered and mobile, with vibrational and rotational (rattling) and translational (diffusing) components.⁵² On cooling a melt, the material may behave in two ways. In the first probability, the liquid state may transform to a crystalline form at Tm. The exothermic crystallization process leads to a sudden contraction of the system due to decrease in specific volume and enthalpy (Fıg. 1).⁵³ Below Tm, the decrease in these thermodynamic properties is less marked. The second probability is that the crystallization is avoided either because the cooling rate is too fast or the crystallization itself is not favored because of molecular shape, size, complexity, or orientation.⁵⁴ In this case, upon cooling, no discontinuity in enthalpy or volume is seen at Tm, and the system is said to form a supercooled liquid. On further cooling of the supercooled liquid, the viscosity increases, reducing the molecular motions; and at some temperature, the molecules move so slowly that they do not have the chance to rearrange themselves before the temperature is lowered further. This range of temperatures over which the equilibrium of the system is lost

Volume or Enthalpy

Liquid

Supercooled liquid

Glass 1

Glass 2

Crystal

Tk

Tg2 Tg1

Tm

Temperature FIGURE 1. Schematic representation of enthalpy (or volume) versus temperature differences for a liquid capable of crystallizing and forming different glasses at different cooling rates (TK: Kauzmann temperature, Tg: glass transition temperature, Tm: fusion temperature).

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is termed the glass transition temperature (Tg). Below Tg, the ergodicity is lost and the material enters the “glassy” state.⁴⁷ At this point, the molecular disorderliness is dramatically reduced, and principally vibrational motions take place. The kinetic analysis during cooling from a melt has been proposed separately by Turnbull⁵⁵ and Uhlmann.⁵⁶ Turnbull suggested that “a glass formation is made possible by avoiding a single nucleation event,” while Uhlmann proposed that “glass is formed by avoiding crystallization less than the critical amount” (generally a volume fraction of Tg, when a critical value of Vf is attained. Another interpretation of the glass transition event in kinetic terms is based on relaxation times. The “structural relaxation time” is defined as the time taken by the molecule to diffuse from the center of its vibration to another center across intermolecular distance.⁵² This relaxation time is directly related to the energy level of the system, with longer times observed as the system is cooled. Tg is defined as the point at which mean relaxation time (τ) changes by two to three orders of magnitude and equals the time of observation (t0).⁵² The time scales of molecular motions can be related to the practical time periods (during glass formation and storage) using a dimensionless quantity, the Deborah number (DN)⁴⁴,⁶⁶: DN =

τ tref

(4)

where tref is the reference time or the time of experiment. Values of DN significantly greater than unity indicate success of the process in terms of glass formation or stability. However, in practicality, the use of DN may not be that simple. Superimposed upon the concept of mean relaxation time are the complex issues of distribution of relaxation times in the amorphous material and changes in these distributions over time.⁴⁴

2. Fragility of Amorphous Materials

Angell⁶⁷,⁶⁸ proposed a classification of “strong” and “fragile” glass formers based on the temperature dependence of mean relaxation time (or viscosity) above Tg. Strong glass formers show an Arrhenius type of relationship, with activation energy independent of temperature. Fragile glass formers conversely show a nonlinear dependence of viscosity upon temperature with a deviation from Arrhenius behavior characterized by temperature-dependent activation energy. This pattern can be depicted in the form of a viscosity/temperature relationship, commonly known as Angell’s plot⁴² (Fıg. 3). At the molecular level, strong glass formers exhibit an open network structure, with a built-in resistance to structural change with increasing temperature. Others, characterized by simple nondirectional coulomb attractions or by van der Waals interactions in the π electrons (primarily aromatic ring substances, such as most pharmaceuticals), provide another extreme of behavior: fragile liquids. Fragile liquids have a structure that teeter on the brink of collapse at their Tgs, and

142

Log Viscosity


12

12

9

9

6

6 Strong

3

3

0

0 Fragile

-3

-3

0.2

0.4

0.6

0.8

Tg/T FIGURE 3. Angell’s plot—viscosity of amorphous materials as a function of normalized temperature above Tg. The increase in curvature of graph depicts higher fragility of the liquid (Tg: glass transition temperature, T: temperature). (Adapted from Ref. 42.)

which, with little thermal provocation, have a tendency to reorganize to structures that fluctuate over wide variety of orientations. Materials showing a fragile behavior indicate a greater tendency to devitrify over their shelf life. Most pharmaceutical amorphous systems show a fragile behavior.⁶⁹ For the fragile glasses, the temperature dependence of molecular mobility (quantified in terms of τ) as well as viscosity can be explained by the Vogel–TammannFulcher (VTF) equation⁷⁰-⁷²: ⎛ DT0 ⎞ τ = τ0 .exp ⎜ ⎟ ⎝ T − T0 ⎠

(5)

where τ0, D, and T0 are constants. Because the mean relaxation time and viscosity follow the same trend with temperature, Equation 5 can also be expressed as

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⎛ DT0 ⎞ η = η0 .exp ⎜ ⎟ ⎝ T − T0 ⎠

(6)

where η0 is a constant. The constant D in the VTF equation is termed the strength parameter, with low values (100) indicating strong glass-forming tendencies. The glass-forming tendency can also be described in terms of fragility parameter, m,⁷³ and KAHR parameter, θ.⁷⁴ Another indicator of the material’s fragility is the change in heat capacity (∆Cp) at Tg. Strong liquids show a very small change in ∆Cp, whereas fragile liquids show larger jumps⁴⁷ (Fıg. 4).

III.B. Molecular Mobility Over the past decade, the single most important realization from the viewpoint of understanding amorphous systems has been in terms of their molecular mobility. Molecular mobility of amorphous pharmaceuticals is a key factor in determining their stability, reactivity, and physicochemical properties. Molecular motions in amorphous

2.0

Fragile

Cp (liq)/Cp (crys)

1.8

1.6

1.4

1.2

Strong

1.0 0.8

1.0

1.2

T/Tg FIGURE 4. Heat capacity changes for various glass forming liquids at Tg. The increasing jumps in relative Cp values depict shift from strong to fragile behavior (Cp: heat capacity at constant pressure, Tg: glass transition temperature, T: temperature). (Adapted from Ref. 54.)

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systems are usually characterized by measuring the time dependence of some bulk property, such as enthalpy or volume, or by using spectroscopic techniques, to monitor the motions of particular functional groups. Various parameters used for prediction of stability of amorphous compounds are (1) mean relaxation time constant (τ) and relaxation time distribution parameter (β),⁷⁵ and (2) temperature characteristic parameters (∆T, Hr , H ′ and S) and crystallization rate constant (k).⁷⁶,⁷⁷ The molecular relaxation processes are typically nonexponential and are usually characterized using the empirical Kohlrausch–Williams–Watts (KWW) equation⁶⁶: ⎡ t β⎤ φ( t ) = exp ⎢ − ⎛⎜ ⎞⎟ ⎥ ⎣ ⎝τ⎠ ⎦

(7)

where φ(t) is the extent of relaxation at time t. The β values are the indicators of the extent to which the data deviates from a true exponential function, with a value of unity corresponding to an exponential function. The technique is usually focused on studying the temperature dependence of the duration of molecular motions at any point in time. At temperatures above Tg, τ typically follows a non-Arrhenius temperature dependence that may permit a 10-fold increase in molecular mobility for as little as a 3–5 K rise in temperature in the region just above Tg. At Tg, τ is typically about 100–200 seconds.⁷⁸ At temperatures below Tg, the apparent activation energy for molecular rearrangement will vary according to sample history, but is typically significantly less than that above Tg.⁷⁹ Because the Kauzmann paradox, VTF equation, and KWW equation are all thermodynamically explainable phenomena, a comprehensive model proposed by Mansfield,⁸⁰ which simultaneously accounts for the three empiricisms associated with glass transition, can be used to understand the behavior of fragile glass forming liquids in totality. Estimation of τ values provides a concrete perspective on the material’s likely performance characteristics. Short average relaxation times, say a few hours, at ambient conditions are suitable only for material stability during a short laboratory experiment but will fail on accelerated stability storage conditions. On the other hand, for materials exhibiting high average relaxation times, reducing the storage temperature should provide a sufficient reduction in molecular mobility to withstand storage at this temperature for several years without any noticeable structural changes. The physical stability of amorphous materials in terms of structural relaxation is usually ascertained by studying the mobility of disordered molecules after storage at constant temperature and humidity, which may be far from practically accessible storage conditions. A true idea of shelf life of amorphous material can only be established on rigorous testing after allowing small excursions from expected storage conditions. Use of master curves prepared for

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different storage conditions and their subsequent use in predicting the relaxation or aging behavior with expected variations in storage conditions has been found as the first step toward assessment of the “effective age” of an amorphous raw material.⁸¹ Furthermore, the concept can be extended to relaxation of partially crystalline samples, because during the relaxation process, the system explores all accessible structural configurations, and the measured relaxation enthalpy is an average based on all configurations and resulting assemblies at a given time point. When crystallization occurs, the number of possible configuration decreases; hence, the average relaxation enthalpy no longer represents the bulk sample. A mass-based normalization thus fully accounts for the percentage crystallinity of the sample and subsequent relaxation behavior. Molecular mobility may not be the only answer to the structural relaxation of amorphous solids. A poor correlation between the molecular mobility (both below and above Tg) of amorphous nifedipine and its crystallization rate partly indicated that the molecular motion provides only a necessary but not a sufficient condition for physical and/or chemical instability.⁸² Crystallization kinetics studies can be a boon in this aspect to model the rate as well as mechanism of devitrification.⁸³

1. Devitrification Kinetics

Modeling of devitrification kinetics of amorphous solids provides a better idea of the rate and mechanism of this reversion process. The rate of devitrification of amorphous solids is substance specific and is influenced by the environmental conditions.

a. Model-Fıtting Approach

It is usual to postulate a model for a reaction that depends on the rate-determining step. The crystallization kinetic data (expressed as extent of conversion, α [where 0 ≤ α ≤ 1] versus time, t) are fit to various reaction models at each temperature. The model of best fit is then selected and is often assumed to represent the actual model that describes the process under examination. Parameters derived from the best model, such as the activation energy, Ea, and the pre-exponential factor, A, are then used to predict the kinetics under different conditions and elucidate the molecular mechanism of the reaction. Mathematically, the model-fitting approach employs the following equation: −E dα = k(T ). f ( α) = A .exp ⎛⎜ a dt ⎝ R.T

146

⎞ . f (α) ⎟ ⎠

(8)


where k(T) is the rate constant and f(α) is a kinetic function, which is termed the reaction model when its mathematical form is defined. Integrating Equation 8 gives α

g (α) = ∫ 0

t

t

−E dα = ∫ k(T ).dt = ∫ A .exp ⎛⎜ a ⎞⎟.dt f (α) 0 ⎝ R.T ⎠ 0

(9)

where g(α) is the integral kinetic function or integral reaction model when its form is mathematically defined. The various reaction models that are commonly used in solid-state kinetics are listed in Table 1. The recrystallization kinetics of amorphous furosemide (FUR) from spray-dried solid dispersions with Eudragit RS 100 and RL 100⁸⁴ and of amorphous indomethacin (IM) from various IM-SiO₂ systems⁸⁵ fitted the Jander equation and the Kolmogorov–Johnson–Mehl–Avrami (KJMA) equation, respectively. (b)

TABLE 1. Common Solid-State Reaction Models in Their Integral Forms {g(␣)} for Devitrification of Amorphous Solids Model notation

g(α)

Mechanism

A2

[-ln(1-α)]1/2

Avrami-Erofeev (n = 2)

A3

1/3

[-ln(1-α)]


A4

[-ln(1-α)]1/4


D1

α

1-D diffusion

D2

(1-α).ln(1-α) + α

2

1/3 2

]

2-D diffusion 3-D diffusion (Jander)

D3

[1-(1-α)

D4

1-2α/3-(1-α)2/3

3-D diffusion (Ginstling-Brounshtein)

F1

-ln(1-α)

1st-order reaction (Mampel)

F2

1/(1-α)-1

2nd-order reaction

P1

ln[α/(1-α)]

Random nucleation (Prout-Tompkins)

PL2

α1/2

Power law (n = 1/2)

PL3

α1/3

Power law (n = 1/3)

PL4

α

Power law (n = 1/4)

R1

α

1-D phase boundary reaction (zero-order)

R2

1-(1-α)1/2

R3

1/3

1/4

1-(1-α)

2-D phase boundary reaction (contracting cylinder) 3-D phase boundary reaction (contracting sphere)

Key: 1-D: one-dimensional, 2-D: two-dimensional, 3-D: three-dimensional Adapted from Refs. 86-88

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Solid-state reactions are usually quite complex, and different kinetic processes can be rate-limiting at various stages of transformation. Therefore, constructing a single representative model describing the entire process is often difficult. In many cases, a model is selected to describe the kinetic data over a certain range of the conversion (usually in the middle, such as 0.15 < α < 0.85). Predictions based on such a fractionally satisfactory model are often erroneous because the initial or final phases of the reaction are simply ignored, which may be important for predictability. The gravity of failure of model-fitting approaches can be understood from the case of humidity-mediated crystallization of amorphous griseofulvin,⁸⁹ wherein the number of moles of drug reacting, as calculated by the reaction model, was quite larger than the actual sample load in the calorimeter. This extra content of reacting moles was later attributed to the water content of the samples. Thus, elucidation of mechanisms by reaction models can be quite erroneous in complex reactions.

b. Model-Free Approach

The model-free approach, on the other hand, is based on the assumption that the reaction model is identical at a given α for a given reaction under different conditions. This assumption is more reasonable than the assumption that a single model fits over the entire range of conversion. Therefore, the model-free approach can detect any variation of Ea as the reaction proceeds, providing insight into a possible change of reaction mechanism at different stages of conversion, and can be very helpful in understanding solid-state reactions.⁹⁰ In the case of study of crystallization kinetics of amorphous nifedipine by the model-free approach,⁹¹ Ea was found to be fairly constant in the range α = 0.05–0.80, signifying the possibility of model-fitting in this constant Ea range of crystallization process. Thus, Ea versus α profile obtained from model-free calculation can act as a useful guide for selection of conversion range applicable to model-fitting and the most appropriate reaction models. For this reason, model-free calculations should be performed before model-fitting of the kinetic data, unless there is a good reason to believe that a particular model can describe the entire range of the reaction under study.

III.C. Molecular Level Interactions in Crystalline and Amorphous Drug Phases The differences in the macroscopic behavior of pharmaceuticals with regard to their solubility,⁴⁶ stability,⁹² and physicotechnical properties⁹³ in glassy and crystalline states are well documented. It is increasingly being understood and

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established that these macroscopic differences are a reflection of the variations in basic molecular level arrangements. Pharmaceuticals fall under the class of low molecular weight organics, where the factors determining the glass structure and properties are different from those observed for more commonly studied inorganic and metallic compounds. From the structural viewpoint, pharmaceutical systems feature extensive H-bonding, complex molecular geometry, and conformational flexibility,⁴² which together define the ease of glass formation and its subsequent stability. In their studies with low molecular weight organic compounds, including glucose, fructose, and substituted ethylenediamine, Karis et al.⁹⁴,⁹⁵ investigated the factors responsible for differences in the behavior of glass formation from melts. They concluded that intra- and intermolecular H-bonding, interlocking due to structural shape, steric hindrance to rotation and/or H-bonding, and the inter-conversion between conformational isomers provided a satisfactory explanation to the glass formation behavior, including departure from the D value, strong–fragile rule. In another study with pharmaceuticals,⁹⁶ differences in the H-bonding patterns in crystalline and amorphous phases of seven dihydropyridine analogs were investigated. Using infrared and Raman spectroscopy and support from single crystal X-ray data, it was concluded that H-bonding can be weaker or absent in either the crystalline or amorphous phase, depending on the molecular structure. The differences in H-bonding strengths between the different analogs were attributed to crystal packing factors. While investigating the effect of temperature on molecular interactions in these two phases,⁹⁷ it was found that molecular arrangement in the crystalline phase was unperturbed by temperature until Tm, whereas changes were apparent in the amorphous phase above Tg. The results presented in the form of wave number/temperature correlation⁹⁸ showed a perceivable deviation in the N-H bond stretching frequency at Tg and Tm, indicating changes in H-bonding occurring at these temperatures. In a similar study,⁹⁹ differences in H-bonding patterns in crystalline and amorphous states of three cyclooxygenase-2 inhibitors were correlated to the physical stability of the amorphous phase. Restriction of molecular motions due to H-bonding in amorphous celecoxib (CEL) and valdecoxib contributed to their relative stability over rofecoxib, which exhibited no H-bonding. These studies indicate that the amorphous state differs from the crystalline state at the molecular level, and within the amorphous state, differences are evident in glassy and supercooled liquid regions. It can be anticipated that not only are these interactions important in determining the properties of pure amorphous phase, but they also provide an opportunity to develop stabilized amorphous systems based on complementary molecular interactions and facilitate the improved delivery of poorly soluble drugs.

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III.D. Solubility Advantage with Amorphous Drugs The disorderliness in the amorphous form of a drug is manifested as “excess” thermodynamic properties relative to the crystalline state. These properties include excess enthalpy, specific volume, entropy, and free energy. This higher free energy (Fıg. 5) is responsible for excess solubility of the amorphous state over the crystalline state.⁴⁶ The excess free energy in the solid amorphous state reduces the energy required for fluidization of the drug molecule to participate in the solubilization process.¹⁰⁰ Solubility is a time-independent thermodynamic equilibrium phenomenon expressed as the amount of dissolved solute in equilibrium with the solid phase. This is different from the “kinetic solubility,” which is expressed as solubility attained in a given time period, and does not necessarily represent the equilibrium state. Dissolution is a kinetic phenomenon that dictates the speed with which the solute goes into solution and is a more meaningful parameter for drug absorption compared to solubility. In the case of amorphous systems, solubility is much more than an adjunct to dissolution, because it carries a thermodynamic meaning and quantifies the degree of metastability of the amorphous phase relative to the crystalline form.

Free Energy

Glass

Supercooled liquid

Crystal

Liquid

Tg

Tm

Temperature FIGURE 5. Schematic free energy diagram for crystal, glass and supercooled liquid (Tg: glass transition temperature, Tm: fusion temperature). (Adapted from Ref. 46.)

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According to Gibbs’s free energy equation for dissolution,¹⁰¹ ∆Gdiss = ∆H diss − T .∆Sdiss

(10)

where G, H, T and S are the Gibbs free energy, enthalpy, temperature, and entropy, respectively, and ∆ represents the changes in these quantities during the dissolution process. This thermodynamic enhancement of solubility also increases the theoretical rate of dissolution according to the modified Noyes–Whitney relationship,¹⁰² dm ⎡⎣ D. A . (C s − C ) ⎤⎦ = dt h

(11)

where the rate of change of mass dissolved m with time t is related to the diffusion coefficient D through a static layer of liquid of thickness h, and Cs is the equilibrium solubility and C the concentration of solute at time t. An increase in the apparent solubility and surface area of drug by amorphization will result in a rapid dissolution process. However, the experimental solubility advantage of amorphous solids is typically less than that predicted from thermodynamic considerations.⁴⁶ In a study by Chawla et al.,¹⁰³ the initial peak in solubility of the amorphous form of CEL dropped to equilibrium levels of crystalline form within 30 minutes because of rapid devitrification induced by dissolution medium. This requires the use of carriers that can serve as stabilizers of amorphous drug form.

III.E. Solid Dispersions The term solid dispersion signifies a range of pharmaceutical products with one or more drugs homogeneously dispersed within a matrix of carrier(s), prepared by the melting (fusion), solvent, or melting/solvent method.¹⁰⁴ On the other extreme, reports exist of use of low content of the carrier material, leading to systems with carrier dispersed in the drug matrix.¹⁰⁵ Preparation techniques for solid dispersions, including the fusion/melt method,¹⁰⁶,¹⁰⁷ the hot melt extrusion,¹⁰⁸ the solution evaporation method,¹⁰⁹ and the supercritical fluid technology¹¹⁰ may yield a totally or partially amorphous drug present as a molecular or particulate dispersion within a carrier matrix. Similar to the broadness of this definition, solid dispersions can also exist in various forms (Table 2). The method of preparation can significantly affect the structure

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TABLE 2. Classification of Solid Dispersions Based on their Phase Composition Type

Characteristic

Eutectic mixture

Two or more crystalline phases

Solid solution

Single crystalline phase

Complex

Single amorphous or crystalline phase

Glass solution

Single amorphous phase

Amorphous suspension

Two partial or complete amorphous phases

Adapted from Ref. 111

of the solid dispersion as well as the physical form of the drug present in the final product. Determination of solid dispersion type and characterization of the phases present is crucial to understanding the behavior of the product. The maximum solubility advantage is expected from solid dispersions in which the drug is present as a single phase in the amorphous state.¹¹² Formulation of a drug as glass solution can lead to an increase in its solubility, because: • Unlike in the crystalline state, there is no lattice energy to overcome in the amorphous state, which reduces thermodynamic barrier to dissolution. • The particle size of components is maximally reduced to the molecular level. • The intimate presence of a hydrophilic carrier leads to an increase in wetting of the drug-carrier system and possibly an increase in its solubility in the diffusion layer surrounding the dissolving particle. In practical terms, use of drug in the form of glass solution results in molecularly dispersed drug in gastrointestinal fluid, which is present in the solution form, after the carrier dissolves. On complete dissolution of solid solution, drug is present as a supersaturated solution or is precipitated out as fine colloidal particles or oily globules of submicron size.¹¹³

1. Binary Solid Dispersions

Over the last three decades, various inert chemical substances have been explored for their carrier properties. The carriers are most often hydrophilic substances that vary widely in their physicochemical properties, ranging from low molecular weight

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sugars to high molecular weight polymers.¹¹⁴ Despite numerous reports on the suitability of low molecular weight carriers in enhancing drug solubility, evidence on their effect on stabilization of amorphous drug is lacking. Thus, most of them can be called only solubilizing carriers without being supplemented with the property of a stabilizing carrier. Table 3 provides a comprehensive idea of solubilizing carriers that have been successful in enhancing drug solubility by preparation of solid dispersions. PEG and poly(vinyl pyrrolidone) (PVP) are the major players in drug solubilization because of their inherent drug solubilization capacity and ability to stabilize the drug in their amorphous form. Very few low molecular weight substances have been successful in enhancing the solubility of the amorphous form, because of their inability to control glass devitrification. As detailed in section III.F.3., specific drug-carrier interaction

TABLE 3. Solubilizing Carriers Reported for Enhancing Drug Solubility in Solid Dispersions Solubilizing carrier

Drug 116

117

PEG

Griseofulvin, phenytoin, prednisolone,118 nortriptyline HCl,119 piroxicam,120 oxazepam,121 fenofibrate,122 ketoprofen,123 glyburide,124 nifedipine,125 carbamazepine,126 ibuprofen,127 zolpidem128

PVP

Griseofulvin,129 sulphathiazole,130 hydrochlorothiazide,131 carbamazepine,132 FUR,133 NSAIDs (mefenamic acid, azapropazone, glafenin and flotafenin),134 oxodipine,135 etoposide,136 benidipine HCl,137 atenolol,138 piroxicam,139 clofazimine,140 lonidamine,141 CEL142

PVP/VA

Carbamazepine,143 atenolol138

HPMC

Benidipine,137 nilvadipine,144 albendazole145

PVM/MA

Griseofulvin,146 clofazimine147

Crospovidone

FUR148

Croscarmellose Na

Itraconazole149

Sorbitol

Prednisolone118

Mannitol

Triamterene150

Lactose

Nitrazepam132

Urea

Ofloxacin151

Chitosan

Nifedipine152

Gellita collagel

Oxazepam153

Egg albumin

Mefenamic acid154

PEG: poly(ethylene glycol), PVP: poly(vinyl pyrrolidone), FUR: furosemide, NSAIDs: non-steroidal anti-inflammatory drugs, CEL: celecoxib, PVP/VA: poly(vinyl pyrrolidone/vinyl acetate), HPMC: hydroxypropyl methylcellulose, PVM/MA: poly(vinylmethyl ether/maleic anhydride)

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might help in stabilizing the amorphous form, but a low molecular weight carrier is usually ineffective. It was found that the monomer of PVP, N-vinyl pyrrolidone, was able to enhance drug solubility, but was a poor amorphous form stabilizer.¹¹⁵ Thus, a suitable length of monomer-chain was required to restrict molecular motions. The polymers can interact with drug molecules via electrostatic bonds (ion/ion, ion/dipole, and dipole/dipole) or van der Waals forces and hydrogen bridges to form water-soluble complexes.¹⁵⁵ The role of PVP and hydroxypropyl methylcellulose (HPMC) as complexing agents is evident from a study¹⁵⁶ in which the aqueous solubility of hydrocortisone, acetazolamide, prazepam, and sulfamethoxazole was significantly increased, both in their ionized and nonionized forms. PEG was also found to be an efficient drug solubilizer, even for a relatively soluble drug, such as aspirin.¹⁵⁷ Despite numerous reports on enhancement in drug solubility using PEG, data are lacking on its effect on the stabilization of amorphous form. On the other hand, PVP has been unequivocally accepted as an amorphous form stabilizer because of its specific interactions with drug molecules limiting their molecular mobility and enhancing overall Tg of binary solid dispersion. The properties and content of polymers have been found to significantly affect the drug dissolution profiles from solid dispersions.

a. Effect of Polymer Molecular Weight

Selection of an ideal polymer with the correct structural features is essential to the performance of solid dispersions. An increase in molecular weight usually causes an increase in Tg of the polymer, thus favoring its use as stabilizing carrier. On the other hand, the differences in Tg become progressively less significant at high molecular weights.¹⁵⁸ Tg is not the only parameter of concern affected by molecular weight. The molecular weight of polymer is also directly related to its intrinsic viscosity and has a marked bearing on drug dissolution. A low molecular weight polymer will dissolve rapidly, saturating the dissolution medium, and result in the release of drug as a single entity (Fıg. 6a). On the other hand, a high molecular weight polymer will form a high viscosity diffusion boundary layer around the solid dispersion particles, resulting in diffusion-controlled release of drug (Fıg. 6b). PEG. PEGs in the molecular weight range of 4000–6000 have been frequently used for manufacturing of solid dispersion, because of their melting points over 50 °C, and still maintaining their high water solubility and low hygroscopicity. Low molecular weight PEGs lead to sticky consistency of product, which are difficult to formulate.¹³⁶ The effect of PEG molecular weight on drug release from solid dispersions has received mixed response. Dissolution rates of griseofulvin,¹¹⁶ hydroflumethiazide,¹⁵⁹ phenylbutazone,¹⁶⁰ nortriptyline HCl,¹¹⁹ and etoposide¹³⁶ were found to decrease

154


(a)

(b)

FIGURE 6. Effect of molecular weight of polymer on drug-release mechanism from solid dispersions (a) Drug-controlled dissolution with low molecular weight polymer and (b) Carrier-controlled dissolution with high molecular weight polymer.

with increasing PEG chain length. Ford¹⁶¹ reported a maximum or minimum in drug dissolution rate at an intermediate molecular weight of polymer. On the other hand, glyburide release was faster from PEG 6000 than from PEG 4000¹²⁴ because of the better dissolution of drug in the carrier and viscosity-dependent prevention of drug precipitation following carrier dissolution. No effect of PEG molecular weight was evident on release of paracetamol,¹⁶² nifedipine,¹⁶³ and naproxen.¹⁶⁴ PVP. Aqueous solubility of PVP becomes poor with increase in chain length, and a further disadvantage of high molecular weight PVPs is their much higher viscosity at a given concentration.¹⁶⁵ High molecular weight PVP was found to lower sulfathiazole,¹³⁰ chloramphenicol,¹⁶⁶ IM,¹⁶⁷ ibuprofen,¹⁶⁸ and phenytoin¹¹⁷ release as compared with solid dispersions prepared employing lower molecular weight PVP. This was attributed to the higher viscosity generated by high molecular weight PVP in the diffusion boundary layer adjacent to the dissolving surface of the dispersion.

155


b. Effect of Drug:Polymer Ratio

The optimization of relative proportions of drug and polymer in the solid dispersion is based on their influence on the drug’s physical form. A high drug percentage will lead to the formation of small crystals within the dispersion, disfavoring its dispersion at molecular level. On the other hand, a high carrier percentage can lead to complete absence of drug crystallinity and, thereby, enormous increases in solubility and drug release rate. Solid dispersions of naproxen in PEG 6000,¹⁶⁹ ibuprofen in PVP,¹⁶⁸ and albendazole in PVP¹⁷⁰ were found to show faster drug release at low drug loadings as compared to that at higher drug loadings. Furthermore, increase in polymer content was found to increase the glass transition and crystallization temperatures and decrease the heat of crystallization of amorphous IM.¹⁰⁵ However, the upper limit to carrier percentage that can be employed is governed by the ability to subsequently formulate the solid dispersion into a dosage form of administrable size. The authors found that a low content of PVP was suitable in stabilizing the amorphous CEL, even at accelerated stability conditions of storage.¹⁴² Furthermore, increase in PVP content above 20% w/w in the amorphous dispersion had little effect on enhancement in CEL solubility.

2. Ternary Solid Dispersions

The realization of the fact that certain carriers can only provide a solubility advantage without the stabilization of the amorphous form for prolonged time period has propelled the use of ternary solid dispersions. These dispersions are a combination of an amorphous-form stabilizing carrier and a solubilizing carrier. The former maintains the amorphicity of the drug in dissolution medium, and the latter contributes in added solubility enhancement. The role of surfactants, especially sodium lauryl sulfate (SLS), as efficient solubilizers was exploited in the preparation of griseofulvin-PEG-SLS¹⁷¹ and naproxen-PEG-SLS¹⁶⁴ ternary solid dispersions. By enhancing the drug solubility in PEG, the surfactant transformed the solid particulate dispersion into molecular dispersion¹⁷² with rapid wettability and enhanced dissolution properties. Similar findings have been reported for ketoprofen-Macrogol 6000-kollagen hydrolizate,¹⁷³ itraconazole-Eudragit E100- poly(vinylpyrrolidone-co-vinylacetate) (PVP/VA),¹⁷⁴ and ibuproxam-PVP-PEG¹⁷⁵ ternary solid dispersions. In a study by Bansal et al.,¹⁷⁶-¹⁷⁹ a synergistic enhancement in the aqueous solubility of CEL was achieved using a drug/PVP/meglumine ternary system, wherein the meglumine was found to further enhance the solubility of PVP-stabilized amorphous CEL over that of crystalline drug.

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III.F. Stabilization of Amorphous Drugs The solubility advantage provided by high energy amorphous form is often countered by its poor stability. The higher free energy of amorphous form makes it inherently unstable, favoring conversion to lower energy, more stable crystalline form. Crystallization may occur either prior to or during dissolution process. As mentioned in Section III.B., the rate of crystallization increases significantly above Tg because of the enhanced molecular mobility in the supercooled liquid state above Tg, relative to that in the glassy state below Tg.⁵⁷ Restricting the molecular motions in the glassy state could be a viable means of stabilizing the amorphous form. The three main approaches for the stabilization of the amorphous substances⁴² follow.

1. The T0– or Tg–50 K Rule

Storage of amorphous materials at temperatures as low as 50 K below Tg can provide sufficient physical stability against reversion to crystalline form. For most of the fragile glasses, T0 (temperature of zero molecular mobility) is approximately 50 K below Tg. Thus, limiting the molecular mobility by regulating the storage conditions can be a viable option for maintaining the drug’s physical integrity. This approach may not be applicable widely, because for majority of compounds, T0 will lie near to refrigeration temperature, which is impractical during different stages of product development, handling, and storage. However, in a true sense, storage below Tg is far from a guarantee of physical stability, because of evidence of molecular mobility of amorphous substances even below Tg.⁷⁹ The relationship between Tg and stability of glassy pharmaceuticals is quite complex. Studies comparing the stability of glassy IM and phenobarbital, both with similar Tg values, showed a considerable variation, even when stored below their Tg values.¹⁸⁰ Glassy IM was reported to be stable over a 2-year period at room temperature, while phenobarbital devitrified within 1 week. These differences were attributed to variations in steric structure and H-bonding within two materials. In addition, water may further lower the Tg of amorphous sample as a result of its plasticization effect, causing failure of this approach.¹⁸¹ Thus, regulation of storage temperature for physical stability of amorphous substances has limited application.

2. Anti-Plasticization Approach

Increasing the Tg of drug system by addition of a high Tg additive¹⁸⁰ is another approach for providing physical stability to amorphous pharmaceuticals. An ideal mixture of a high and low Tg components results in a substance of intermediate

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Tg value, leading to reduced molecular mobility of the phase relative to drug alone, with reduced tendency to crystallize. The Tg of a chemical substance is a manifestation of its structural complexity and associated chemical interactions. Polymers are unique in this aspect because of their high molecular weight and variable topology,¹⁸² ranging from linear, to branched, to network configuration, which adds complexity in chemical interactions as a result of varying microstructure.¹⁸³ Tacticity, the arrangement of functional groups along a carbon backbone, also affects chemical interactions between polymer chains, resulting in different polymer morphologies¹⁸⁴ characterized as amorphous, semi-crystalline, and crystalline polymers. These structural differences have important bearing on chain flexibility and, thus, relaxation of polymer strands. Various molecular factors¹⁸⁵ interplay with the Tg of polymers, like stiff backbones (double bonds and ring structures) and rigidly held bulky side-groups restrict polymer strand movement, and increase in carbon chain length leads to increase in Tg of homologous polymers. The Tg of a mixture (Tg mix) can be related to Tgs of its components by GordonTaylor/Kelley-Bueche¹⁸⁶,¹⁸⁷ and Fox–Flory equations,¹⁸⁸ favoring the amorphous mixing theory based on the free volume concept, and gives Tg mix assuming no specific interaction between the two components.

(

) (

)

⎡ w1 .T g 1 + K .w2 .T g 2 ⎤ ⎦ T gmix = ⎣ ⎡⎣w1 + ( K .w2 ) ⎤⎦

(12)

where subscripts represent the two components, w represents their weight fractions, and K is the ratio of their free volumes given by¹⁸⁹

K=

(ρ1.Tg 1 ) (ρ2 .Tg 2 )

(13)

where ρ is the density of the material. Using a thermodynamic model, Equation 12 can be transformed into the Couchman–Karasz equation¹⁹⁰ given by K=

( ∆C p 2 ) ( ∆C p1 ) 158

(14)


Tg

where ∆Cp is the change in heat capacity at Tg. Additional parameters¹⁹¹-¹⁹³ are added in these equations to account for specific drug/carrier interactions. The goodness of fit of experimental data to the Gordon–Taylor/Kelley–Bueche equation indicates the ideality of mixing of two components, as well as providing a predictive tool for assessing the effects of different levels of a second material on Tg. Deviation from ideal behavior signifies differences in the strength of intermolecular interactions between individual components and those of the blend (Fıg. 7). The utility of this anti-plasticization effect can be highlighted with a study wherein the Tg of PVP was reduced linearly with increasing concentration of various drug molecules.¹⁹⁴ The relationship between Tg and the composition can be either linear, as for pentobarbital/citric acid,¹⁹⁵ hexobarbital/citric acid,¹⁹⁵ and heptabarbital/citric acid¹⁹⁵; and hexobarbital/dextrose,¹⁹⁶ phenobarbital/salicin,¹⁸⁰ IM/PVP,¹⁰⁵ ketoconazole/PVP,¹⁹⁷ CEL/PVP,¹⁹⁸ and itraconazole/PVP/VA¹⁷⁴; or nonlinear, as for acetaminophen/citric acid,¹⁹⁶ sulfonamide/citric acid,¹⁹⁶ and sulphathiazole/citric acid,¹⁹⁶ and antipyrine/IM¹⁸⁰ systems. Thus, anti-plasticization effect is nonspecific and can be used for a wide variety of drug molecules.

Ideal Behavior D-C = D-D or C-C Positive Deviation D-C > D-D or C-C Negative Deviation D-C < D-D or C-C

Carrier Content FIGURE 7. Deviation from ideal behavior in variation of Tg of drug (D) and carrier (C) binary mixture with increasing carrier content (Tg: glass transition temperature).

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Molecular mobility of amorphous CEL was significantly decreased with increase in PVP K30 content in CEL/PVP solid dispersions.¹⁹⁸ At 10% w/w level, maximal reduction in molecular mobility of amorphous CEL was provided by PVP K30, followed by PVP K17, HPMC, and trehalose. In another study, at an aging temperature of 65 °C, half-life for enthalpy relaxation of 2:8 GWX-hydroxypropyl methylcellulose phthalate co-precipitate was about six orders of magnitude greater than that of amorphous drug alone, indicating a large difference in relative molecular mobility.¹⁹⁹ Low contents of PVP substantially reduced the molecular mobility of amorphous nifedipine and phenobarbital.²⁰⁰ The time required for the amount of amorphous drug remaining to fall to 90% was enhanced 100–1000 times for solid dispersions than for the pure drugs when compared at same temperature. Polymer content and its molecular weight have been found to be major contributory factors in restricting the molecular mobility of amorphous drugs. Increase in PVP content was found to reduce the extent of recrystallization of amorphous IM,¹⁰⁵ MK-0591,²⁰¹ and CEL,¹⁹⁸ signifying better stability. A lesser proportion of relaxed glass with the progressive use of higher molecular weight PVP in the case of IM²⁰² and MK-0591²⁰¹ reflected the reduced molecular mobility in high molecular weight polymers. Even though thermodynamics still drives drug molecules to instability, kinetics may be altered to such an extent that crystallization becomes significantly slow. The stabilizing effect of polymer is not only limited to the predissolution phase but continues well during the dissolution process. Devitrification of amorphous drug, forced by the plasticization effect of water, is prevented by the polymer, because of a hydrodynamic boundary layer around the drug molecules being released from the solid dispersion.¹¹⁵ A relative increase in the viscosity of the dissolution medium around the drug molecules reduces their diffusion, avoiding interaction and crystal lattice formation.²⁰³ Thus, the inherent amorphous nature and high molecular weight of polymers not only assist in anti-plasticization of otherwise unstable amorphous drug molecules, but also prevent the plasticization effect of water. In some cases, carrier may serve to inhibit precipitation of drug from supersaturated solution.¹⁶⁷,²⁰⁴,²⁰⁵ It has also been speculated that if drug does precipitate, it will precipitate out as a metastable polymorph with a high solubility compared to that of the most stable form.¹⁶⁷,²⁰⁶ In a study by Gupta and Bansal,¹⁴² it was found that the physical mixture of amorphous CEL and PVP gave similar enhancement in solubility, as achieved using the amorphous dispersion. The use of PVP in dissolved form in water also provided the same level of solubility for amorphous CEL. These results signified that PVP acts as an amorphous form stabilizer, both in solid-state and solution-state. The stabilizing effect of PVP was further evidenced by maintenance of peak in drug solubility for longer time periods as compared to the rapid fall seen in case of amorphous CEL (unpublished results).

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3. Specific Drug–Carrier Interaction

Specific reversible chemical interactions between drug and carrier can also limit the molecular motions of drug in amorphous state and thus stabilize the system. PVP combines a hydrophobic backbone with a hydrophilic side group. Importantly, it cannot self-associate through H-bonding in the pure state because of a lack of acidic protons, although it does contain a basic group capable of donating electrons.²⁰⁷ Thus, it has the capability of H-bonding with electron-accepting centers. Chemical interaction between IM and PVP has been evidenced as a major cause of limited selfassociation of IM molecules to form dimer, thus inhibiting its crystallization.²⁰⁸ Specific H-bonding of the carbonyl group of PVP with the H-donating group of FUR was studied by comparing it with spectra of FUR in solution of a model bonding solvent, 1,4-dioxan.²⁰⁹ The spectral differences observed between crystalline FUR and FUR in the bonding solvent were very similar to those reported for spectral subtractions of amorphous FUR–PVP dispersions, both in N–H stretching and S=O (symm) vibrations. The FUR sulfonamide group bound to PVP in preference to the FUR secondary amine, which is capable of forming an intra-molecular H-bond. These solid-state interactions were found to be responsible for stabilization of the amorphous FUR–PVP solid dispersion. These studies were further extended to specific interactions between PVP and IM, wherein acetic acid served as a model of IM carboxylic acid group and methylpyrrolidone as a model of PVP.²⁰⁸ Similar magnitudes and nature of interactions were observed, signifying formation of H-bonds between the hydroxyl group of IM and the carbonyl group of PVP at the cost of cleavage of IM dimer. The proton-donating group, critical for dimer formation, gets engaged in H-bond formation with PVP molecule and thus stabilizes the amorphous IM. Numerous examples have been cited in the literature for specific drug–carrier interactions (Table 4).

III.G. Drug Release from Solid Dispersions 1. Mechanism of Drug Release

Knowledge of the mechanism of drug release from a solid dispersion is essential for understanding the improvement in dissolution of a poorly soluble drug. Drug release mechanism may be influenced by drug’s chemical structure and physical form, the weight fraction of the dispersed drug and the carrier, and the molecular weight of the carrier. In contrast to this, the presence of the drug may also retard the carrier dissolution, through effects on binding and polymer swelling. Studies with PVP,¹³⁰ polyethylene glycol (PEG),²¹⁵ Renex™,²¹⁶and β-cyclodextrin²¹⁷ showed a decline in carrier dissolution rate resulting from strong drug–carrier interactions.²¹⁸, ²¹⁹

161


TABLE 4. Specific Drug-Carrier Interactions for Stabilization of Amorphous Drugs Chemical interaction

Drug–carrier

Remarks

Ref.

Ajmaline-PVP

-OH----O=C-

Dipole-induced dipole complex enhanced ajmaline solubility

210

Nabilone-PVP

-OH----O=C-

H-bonding stabilized amorphous drug for 2 years at room temperature

211

IM-PVP IM-PVP/VA

-OH----O=C-

H-bonding inhibited drug crystallization at 30°C for 20 weeks, using 5% w/w of polymer

202

-COO-Na+ O=C=+N-

Ion-dipole interaction resulted in higher Tg values than those predicted by Gordon-Taylor equation

201

Probucol-PVP

-OH----O=C-

H-bonding stabilized the amorphous form of drug in binary dispersion

212

IM-SiO2

-O=C----OH-

Preferential chemical interaction after prolonged co-grinding immobilized drug molecules to suppress recrystallization

85

IM-Mg(OH)2-SiO2

C-O-Me (Me = Mg/Si)

Enhanced mechanical dehydration due to formation of strong acidic sites by co-grinding promoted bridging bands, and reduced molecular mobility of drug

213

Ketoprofen- and Naproxen-Gelucire®Magnesium aluminosilicate

-O=C----OH-

Increased H-bonding after storage contributed to enhanced drug dissolution

214

MK-0591*-PVP

-

* An investigational drug PVP: poly(vinyl pyrrolidone), IM: indomethacin, PVP/VA: poly(vinyl pyrrolidone/vinyl acetate), SiO2: silica, Mg(OH)2: magnesium hydroxide

The drug release mechanism from solid dispersions can be studied under two broad heads of chemically noninteracting and interacting systems, described below.

a. Chemically Noninteracting Systems

In a chemically noninteracting system, the water-soluble carrier dissolves rapidly, followed by the release of drug molecules. The mechanism of drug release will thus be governed by relative differences in drug and carrier properties and on their pro-

162


portion in the solid dispersion. Accordingly, two mechanisms of drug release from the solid dispersion have been proposed.²²⁰ Carrier-controlled dissolution. The drug release is dependent on the properties of the carrier²²¹ because the carrier may be the major component of solid dispersion. The hydrophilicity, molecular weight, viscosity grade, etc. of the carrier may have a pronounced effect on drug release from solid dispersion. Drug-controlled dissolution. The drug release is dependent on the properties of the drug, as it may be the major component of solid dispersion. From a glassy solution, the carrier molecules dissolve first, followed by the exposure of drug molecules to the dissolution medium. Depending upon the environment, the drug may either crystallize or remain amorphous. Thus, the physical form of the drug in terms of its crystallinity will dictate its dissolution kinetics. In simpler words, high drug loadings in solid dispersion leads to drug-controlled dissolution, with the drug’s physical properties such as particle size, crystallinity, and polymorphism governing its release. On the other hand, low drug loadings allow carrier molecules to control drug release.²²² The relative predominance of the two mechanisms further depends on the solubility (Cs) and diffusion coefficient (D) of each component in the dissolution medium. The following model can explain the two release mechanisms better: N ∝ D.C s

(15)

where N is the proportion of component in the dispersion. Under these circumstances, dissolution rates per unit area (G) will be given by:

G=

D.C s h

(16)

where h is the diffusion layer thickness. The G for other component will depend on its proportion in the solid dispersion and G of highly dissolving component. At the critical mixture ratio—i.e., when N A D A .C sA = N B DB .C sB

163

(17)


where subscripts A and B refer to the two components, respectively, both components coexist at all times at the solid/liquid interface, and dissolution profiles are linear under sink conditions. At all other weight ratios, one or other component forms a porous layer at the surface, which represents an additional barrier, retarding dissolution of the receding phase and resulting in a curved dissolution profile for the receding component. This, therefore, predicts that if drug B has a very low solubility compared to carrier A, then the drug loading up to which carrier-controlled dissolution will apply will be similarly low, while a more soluble drug will show carrier-controlled dissolution up to a higher drug loading. The model also predicts that the release rate of either component in the dispersion is never greater than that of the pure component alone.²²⁰ Identification of the mechanism of dissolution helps in deciding the strategy for improving the performance criteria of the amorphous system. If drug release from a system is carrier controlled, then modifications with the carrier, such as changing its molecular weight, incorporating a proportion of lower molecular weight material may have a beneficial effect on drug dissolution. On the other hand, if the drug release from a system is drug controlled, then the properties of the drug itself, such as recrystallization from unstable solid solutions or amorphous form, must be considered, because they directly affect the dissolution profile.

b. Chemically Interacting Systems

In chemically interacting systems, such as those forming a soluble complex in solution,¹⁰⁴,²²³-²²⁵ dissolution of each component is enhanced by the contribution from the diffusing complex, and dissolution rates above those of the individual pure components are observed. The maximum rates occur at the critical mixture ratio given by²¹⁷: N A ( D A .C sA + D AB .K .C sA .C sB ) = N B ( DB .C sB + D AB .K .C sA .C sB )

(18)

where K is the binding constant and DAB is the diffusion coefficient of the complex. The magnitude of the dissolution rates of each component (Cmax) at the critical mixture ratio are²²³ C max = A

( D A .C sA + D AB .K .C sA .C sB ) h

164

(19)


C Bmax =

( DB .C sB + D AB .K .C sA .C sB ) h

(20)

Dissolution rates of each component decline rapidly as the weight fraction deviates from the critical mixture ratio.

2. Drug Release Modeling

Modeling is a mathematical tool to understand the mechanism of drug release from the drug product. The quantitative interpretation of values obtained in the dissolution assay is facilitated by use of a generic equation that mathematically translates the dissolution curve into a function of some parameters related to pharmaceutical dosage forms. A comprehensive review²²⁶ describes various mathematical models applicable for studying drug release kinetics. Various properties of drug, such as its polymorphic form, crystallinity, particle size, solubility, and amount in dosage form, can influence the release kinetics.²²⁷ Because solid dispersions may vary in terms of drug’s crystallinity, a clear idea of drug’s release kinetics is difficult. Partially crystalline drug samples have been shown to exhibit biphasic release profiles owing to solution-mediated transformations of amorphous forms.²²⁸ Most of the reports on drug release modeling from solid dispersions lack complete drug characterization for its solid-state form. Partial devitrification during the course of dissolution can alter the release kinetics and give erroneous results.

a. Zero-Order Kinetics

Zero-order release kinetics signify drug release independent of its concentration in the dosage form.²²⁹ Qt = k0 .t

(21)

where Qt is the amount of drug released in time t, and k0 is the zero-order release rate constant. Release of clofazimine from poly(vinylmethyl ether/maleic anhydride) coevaporate,¹⁴⁷ and praziquantel from PVP coprecipitate²³⁰ has been reported to follow zero-order kinetics.

165


b. Fırst-Order Kinetics

Fırst-order release kinetics is followed by the drug products releasing the drug in proportion to the amount of drug remaining in its interior.²³¹

ln Qt = ln Q0 − k1 .t

(22)

where Q0 is the initial amount of drug in solution, and k1 is the first-order release rate constant. The dissolution of carbamazepine and nitrazepam from solid dispersions (using lactose, mannitol, galactose, PEG 6000) and coprecipitate (using PVP K30),¹³² and of zolpidem from PEG 4000 and 6000 solid dispersions¹²⁸ was found to best fit the first-order release kinetics.

c. Hixson–Crowell Model

The Hixson–Crowell release model is applicable in powder dissolution studies, where surface area changes uniformly with time, maintaining the initial geometrical form.²³² The mathematical model is build with the recognition of fact that the particle regular area is proportional to the cubic root of its volume. W01 / 3 − Wt1 / 3 = kHC .t

(23)

Wt−2 / 3 − W0−2 / 3 = kHC .t

(24)

where Wo is the initial amount of drug in the dosage form, Wt is the remaining amount of drug in dosage form at time t, and kHC is a constant incorporating surface/volume relation. Equation 23 is used for sink conditions and Equation 24 for nonsink conditions for drug in dissolution medium. When this model is used, it is assumed that the release rate is limited by a drug particle’s dissolution rate and not by diffusion that might occur through polymeric matrix. Release of griseofulvin from PEG and PEG/talc solid dispersion powders²³³ and clofazimine from PVP and PEG solid dispersion powders¹⁴⁰ was found to best fit the Hixson–Crowell release model.

166


d. Baker–Lonsdale Model

The Baker–Lonsdale release model is used to describe the drug release from spherical matrices.²³⁴ 3 / 2 ⎡1 − ( 1 − F ) 2 / 3 ⎤ − F = kBL .t ⎣ ⎦

(25)

where F is the fraction of drug released at time t, and kBL is the release rate constant. Release of zolpidem from PEG 4000 and 6000 solid dispersion powders was found to best fit the Baker–Lonsdale model.¹²⁸

III.H. Barriers in the Design of Amorphous Drug Delivery Systems The use of amorphous systems is not new to the pharmaceutical field. Even after three decades of arduous research, very few have reached the marketplace. Examples³,⁴⁴,²³⁵ of fully or partially amorphous systems include quinapril HCl (Accupril®), zafirlukast (Accolate®), nelfinavir mesylate (Viracept®), GW280430* (investigational drug of GlaxoSmithKline), cefuroxime axetil (Ceftin®), cefpodoxime proxetil (Vantin®), insulin, and excipients such as silicon dioxide, microcrystalline cellulose, and lactose. Although the majority of these drugs are marketed in crystalline form,³,⁸⁸ which is thermodynamically more stable and easy to prepare reproducibly and characterize for certain drugs having poor solubility and dissolution rate, the amorphous form promises to optimize their delivery. The limited market presence of amorphous drug systems is due to various problems associated with their preparation and performance.

1. Lack of Characterization Tools

Most of the analytical principles and scientific theories are directed toward characterization of crystalline materials. The response of these analytical techniques in the characterization of an amorphous material is indirectly implied by the “absence” of the crystalline material, rather than by the actual presence of amorphous material (Table 5). Furthermore, most of these techniques are insensitive toward detection of lower amorphous fractions. The lack of a meaningful characterization tool, responsive to material’s amorphicity, has repercussions in quality control during processing and performance. The Tg, which is perhaps the only “true” characteristic property

167

168

Sudden decrease in viscosity above glass transition Increase in tan δ at glass transition

No response

Continuous decrease in viscosity

Constant tan δ

Birefringence with extinction positions

Increasing solubility with time, plateau after equilibrium

High

Dielectric analysis

Viscometry

DMA

Microscopy

Solubility

Density

249

228

248

247

246

245

244

243

242

241

240

239

62

238

237

Refs.

XRD: X-ray diffractometry, FTIR: fourier transform infrared, NIR: near infrared, DSC: differential scanning calorimetry, MDSC: modulated differential scanning calorimetry, ss-NMR: solid-state nuclear magnetic resonance, TSC: thermally stimulated current, DVS: dynamic vapor sorption, DMA: dynamic mechanical analysis

Low

Higher initial solubility, falls to equilibrium value of crystalline form

Absence of birefringence and extinction positions

Dielectric loss at glass transition

High vapor sorption

Low heat of solution

Recrystallization exotherm

Glass transition

Broad peaks

Low vapor sorption

Depolarization peak

TSC spectrometry

DVS analysis

Sharp peaks

ss-NMR

Reversible event: glass transition; Irreversible event: relaxation endotherm, recrystallization exotherm and fusion endotherm

No response

Sharp fusion endotherm

MDSC

Glass transition with/without recrystallization exotherm and fusion endotherm

High heat of solution

Sharp fusion endotherm

DSC

Broad vibrational bands

Solution calorimetry

Sharp vibrational bands

Vibrational spectroscopy (FTIR, NIR and Raman)

Amorphous sample Broad hump or halo pattern

Observations

Isothermal microcalorimetry

Sharp diffraction peaks

Crystalline sample

XRD

Technique/ Property

TABLE 5. Comparative Response of Characterization Techniques for Crystalline and Amorphous Solids



of amorphous material, may differ with the analytical technique,²³⁶ and analysis parameters such as heating and cooling rates in DSC.⁶¹,⁶²

2. Heterogeniety in Amorphous Solids

As discussed previously, amorphous solids are characterized by an absence of long-range order of the constituent molecules. Because only a particular type of order can define a continuous homogenous phase, the absence of order in the amorphous solid may favor heterogeniety. The structural heterogeniety in amorphous solids arises from nonuniformity in structure and composition gradient in sample during storage and subsequent handling (e.g., temperature gradient during quench-cooling and lyophillization, and surface activation during milling).⁷⁸ This structural heterogeniety gives rise to a distribution of relaxation times in the amorphous state, and thus is called the dynamic heterogeniety. Heterogeniety leads to a phenomenon called polyamorphism. This term is analogous to polymorphism in crystals, exhibited as two (or more) distinct amorphous states of same material. The occurrence of polyamorphism has been reported for ice²⁵⁰ and silicon dioxide.²⁵¹ Speculation regarding the importance of this phenomenon for pharmaceuticals directly stems from the potential differences in solubility, implications on quality control, and opportunity in patenting the new polyamorphic forms. With no reports for polyamorphism thus far for pharmaceutical systems, it still remains a gray area, and the differences in the physical properties of the amorphous form of the same substance possibly arise from the differences in manufacturing procedure and/or the time for which the system has been aged. It is important to mention that it is possible to isolate drugs (and other materials as well) with distinct physical and chemical properties that are not true polyamorphs. These do not represent distinct thermodynamic phases, but are a continuum of the kinetic states differentiated in their extent of energetic departure from equilibrium supercooled liquid condition. This phenomenon has been called pseudo-polyamorphism by Hancock et al.²⁵²

3. Elucidation of Drug Form in the System

The enhancement in a drug’s biopharmaceutical performance by use of solid dispersions has largely been fortuitous.⁹² A large number of reports deal with solubility or dissolution rate improvements using solid dispersions, without attempts to elucidate the solid-state differences in the drug form. The drug may be present as a molecular, crystalline, or amorphous particulate. The solubility advantage and stability profile of these drug forms is expected to be different, raising concerns over their utility. A lack of thorough understanding of the associated molecular processes has also prevented success of strategies for stabilization of the amorphous form.

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4. Engineering of Pharmaceutical Alloys

The formulation of solid dispersions has largely been an arbitrary approach, without due regard to drug/drug and/or drug/carrier interactions. Hancock has opined that “engineering” of amorphous pharmaceutical alloys provides opportunities for drug delivery that cannot be realized with conventional crystalline substances. This is because disordered systems are not confined to predefined templates for molecular arrangements as are crystalline materials, and it is possible to solidify solutions, mixtures, and multiphase systems that could never be isolated in a completely crystalline state.⁴⁴ When at least one of the components in a binary system is capable of glass formation, both, one, or neither material may form a glass. In addition, total miscibility, total immiscibility, or partial miscibility may be encountered. If the drug and the carrier are immiscible, dispersion of drug into carrier can be problematic, with irregular crystallization, uniformity problems, and possibly little improvement in drug dissolution rate. For miscibility of two liquids/melts, the Gibbs free energy of mixing at constant pressure (∆Gm) must be negative.²⁵³ ∆Gm = ∆H m − T .∆Sm

(26)

The entropy change of the mixing (∆Sm) process is usually positive. In order to predict miscibility, it is necessary to evaluate the enthalpy term (∆Hm). When this term is negative or positive, but less than T.∆Sm, mixing can occur. Various thermal techniques, such as hot-stage microscopy (HSM)¹¹¹,²⁵⁴ and differential scanning calorimetry (DSC),¹¹¹ have been used to ascertain drug/carrier miscibility. Using DSC, determination of heat of fusion of drug in solid dispersions of increasing carrier concentration can show the drug and carrier to be miscible at the composition showing zero heat of fusion.¹⁴¹,¹⁴²,¹⁷¹,²⁵⁵ In a study by Moussaoui et al.,²⁵⁶ the mixing enthalpy of drug and carrier was found to correlate with the dissolution kinetics of solid dispersions. The highest mixing enthalpy of nordazepam with PEG in comparison to that with succinic and nicotinic acid was reflected in its dissolution kinetics. Furthermore, the drug/PEG melt was found to have higher mixing enthalpy than the respective coprecipitate and physical mixture, in concordance with its better dissolution kinetics. Solubility parameters can also be used to predict drug/carrier miscibility.²⁵⁷ Components with similar solubility parameter values are likely to be miscible, because interactions in one component will be similar to those in the other component. Consequently, the overall energy needed to facilitate the mixing of the constituents will be small, because the energy required to break interactions within the components will be equally compensated for by energy released by interactions between unlike molecules.

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Hilderbrand solubility parameters²⁵⁸ were used to predict drug/carrier compatibility or miscibility and were found useful for selecting suitable polymers as carriers in solid dispersion of nifedipine²⁵⁹ and phenytoin.²⁶⁰ But the use of Hilderbrand parameters in accurate prediction of the phase diagram and specific level of drug/carrier interaction is limited by the prediction of overall cohesive energy in materials, with little information on relative strengths of various types of forces present (dispersion, polar, and hydrogen-bonding). The Hansen solubility parameter²⁶¹ takes into account all these interactions, in addition to molar volumes and molar attraction constants.¹¹¹ However, due care must be taken while calculating solubility parameters, because a drug’s crystallinity has also been reported to affect its solubility parameter values.²⁶²

5. Limitations of Manufacturing Procedures

Partially or fully amorphous solids may be generated via a number of routes, such as quenching of melts, rapid precipitation from solution by the anti-solvent approach, rapid evaporation²⁶³ (including spray and freeze drying), vapor condensation, mechanical activation (milling and compression of crystals), introduction of impurities during crystallization,²⁶⁴ dehydration of hydrates,²⁶⁵ heavy particle bombardment of a crystalline form, and in situ chemical reaction. The properties of glasses are markedly affected by their thermal history and the temperatures involved in their preparation. This is a major reason for the lack of “comfort factor” associated with amorphous pharmaceuticals. Krec and Srcic⁶² have reported the influence of cooling rate during preparation and heating rate during analysis, and the influence of annealing on Tg and recrystallization temperatures. A standardized protocol for glass transition analysis will be indispensable for quality control because of the dependence of Tg on measuring variables.⁶² The manufacturing of amorphous drug products is plagued by several problems, such as (1) thermal degradation of certain drugs, disfavoring the melt method¹⁰⁴; (2) the requirement of large quantities of a common solvent to dissolve lipophilic drug and hydrophilic carrier in solvent method¹¹⁶; (3) difficulties in optimization of processing parameters, such as rates of cooling, drying, etc.¹⁰⁷; (4) difficulties in dosage from development due to the tacky and hygroscopic nature of these dispersions.¹⁶¹ However, the greatest problem of all is the absence of a suitable large-scale manufacturing process for generation of amorphous drug substance.

6. Physical Transformations During Processing

Physical stresses confronted during the various unit operations of dosage form development may negate the benefits of a metastable amorphous form for per-

171


formance advantages. Unit operations²⁶⁶ such as size reduction, drying, dry and wet granulation, and compression induce thermal, mechanical, or solvent related stresses, and may lead to drug crystallization. A method to avoid these changes should be based upon the comparison of time scale of structural change in the material to the time scale of processing-induced stress.²⁶⁷ In addition, the effect of processing must be considered at the scale-up stage to avoid altered performance.²⁶⁸

7. Chemical Reactivity

The rate of degradation of drugs is reported to be higher in the amorphous than in the crystalline state.²⁶⁹ The possible reasons for this behavior could be increased specific surface area and the enhanced level of molecular mobility in the amorphous regime, which reduces the activation energy for solid-state chemical reactions. In addition, the higher hygroscopicity of amorphous systems leads to enhanced rates of degradation, both directly by mediating the degradation reaction and indirectly by plasticizing the drug and thereby increasing molecular mobility.²⁷⁰ Pikal et al.²⁷¹ reported thermal degradation rates of β-lactam antibiotics a magnitude higher in amorphous form than in crystalline form, with enhanced degradation in the presence of moisture. The chemical instability of the amorphous form of quinapril HCl²⁷² prepared by two methods was found to be similar and correlated with the increased molecular mobility at higher temperatures. The high chemical reactivity of amorphous solids can further lead to extensive drug/ excipient interaction, promoting instabilities in the final formulation. However, in certain cases, a solid state reaction may require a high level of positional specificity between reacting species, which is present in a highly ordered crystalline state. In such cases, reactivity in amorphous state would be reduced relative to crystalline state.²⁷³,²⁷⁴ Therefore, the amorphous systems offer a challenge of enhanced chemical reactivity that needs to be circumvented through use of appropriate packaging and storage conditions.

8. Mechanism of Drug Release

As detailed in section III.G.1., the type of solid dispersion has a profound effect on the mechanism of drug release. The physical form of the drug can significantly alter the release kinetics, thus raising delivery concerns. Thus, only a proper understanding and characterization of the amorphous system could help in designing a “science-based” delivery system with predictable performance.

172


III.I. Controlled-Release Systems based on Amorphous Drugs Dispersion of drug into an inert carrier can either accelerate or retard drug dissolution, depending on the nature of the carrier, whether hydrophilic or hydrophobic, respectively.¹⁰⁴ A controlled release (CR) system of an amorphous drug may be prepared for either insoluble or soluble drugs. In case of insoluble drugs, incorporation into a solid dispersion will render drug amorphization, leading to enhanced solubility and greater flux from the delivery system. For highly soluble drugs, the preparation of a solid dispersion will allow an intimate contact of the drug with the release controlling polymer, thus providing a better control over the release profile. Table 6 cites examples of a few CR systems of amorphous drugs. Numerous attempts have been made to prepare CR systems based on solid dispersions.¹⁶¹,²⁸⁸ Although the underlining concept of a CR system is the release of drug at a controlled slow rate, for insoluble drugs, achieving the desired rate of release may prove difficult as a result of insolubility of the drug. In such cases, increasing the solubility of drug by amorphous solid dispersions above the level required for delivery from the system may be advantageous. Another application of solid dispersion technology combined with CR has been as a means to control the rate of release of highly soluble drugs,²⁸⁹ similar to the preparation of CR matrix tablets. The monolithic structure of solid dispersion provides homogeneous distribution of drug, avoiding the risk of burst release. The advantages quoted in this case include an intimate contact of drug at the molecular level with rate-controlling polymer, ease of mixing, reproducibility, predictability, and control of release profiles.²⁹⁰ The devitrification kinetics of unreleased fraction of drug in the system during dissolution can have an important bearing on its release kinetics and overall performance. The stabilization of the amorphous drug within the system is challenging because of the longer contact period of drug with water before it gets released or absorbed. The stabilizing effect of carrier in the presence of water and prevention of crystallization under in vivo conditions is required in CR systems. A major lacuna in the application of amorphous CR systems remains the incomplete characterization of drug form in the system. The identification of the drug being present either as a molecular or a particulate solid dispersion is essential to ensure predictability of performance over the shelf life. Furthermore, the release mechanism of the system may be influenced by the type of dispersion.

III.J. In Vivo Performance of Amorphous Drug A high-energy amorphous form of a poorly soluble drug is aimed at enhancing its apparent solubility and dissolution rate, with the ultimate objective of enhancing its

173

174

Micro-encapsulates of CA

Multiple-unit floating system

Tablets

Tablets

Tablets

Powder

Buccal films

Powder

Capsules

Powder

Compressed microparticles as tablets

Microspheres

Nifedipine

FUR

Theophylline

IM

Ibuprofen

Diclofenac Na

Lidocaine HCl

Flurbiprofen

Diclofenac Na

Phenacetin

Felodipine

Nitrendipine

Quasi-emulsion solvent diffusion with HPMCP

Spray-chilling with polar lipids

Co-evaporation with PEO-Carbopol

Freeze drying with EC-Chitosan

Co-evaporation with PEO

Co-evaporation with EC-HPC

Spray drying with EC-Chitosan

Co-precipitation with Eudragit S 100

286 287

Inclusion of Eudragit® RS PO and EC in solid dispersion enhanced BA and prolonged Tmax

285

284

283

282

281

280

279

278

277

276

275

Refs.

Release retardation of hydrophobic drug by solubilization in carrier

Homogeneous distribution of amorphous form of a water soluble drug in polymeric matrix provided precise control on release rate

Optimum controlled release from solid dispersion

Extent of drug-polymer H-bonding controlled drug release

Well-controlled drug release from co-evaporates

Optimum controlled release from solid dispersion

Efficient drug release from co-precipitates

Drug-polymer interaction retarded drug release

Co-evaporation with Eudragit® RS/RL ®

Homogeneous distribution of amorphous drug in polymeric matrix

Quench cooling of drug-PEGEudragit® melt

Enhanced dissolution rate of amorphous drug facilitated complete dose release over actual intragastric residence time

Fast drug dissolution from co-evaporate, controlled by CA membrane

Co-evaporation with PVP-MCC or HPC-MCC Co-evaporation with PVP

Sufficient release of amorphous form of weakly basic drug in alkaline media

Remarks

Co-evaporation with Eugragit® S/L/L 100-55/RL/RS

Method of solid dispersion preparation

CA: cellulose acetate, PVP: poly(vinyl pyrrolidone), MCC: microcrystalline cellulose, HPC: hydroxypropyl cellulose, FUR: furosemide, PEG: poly(ethylene glycol), IM: indomethacin, EC: ethylcellulose, PEO: poly(ethylene oxide), HPMCP: hydroxypropyl methylcellulose phthalate, BA: bioavailability, Tmax: time to reach maximum plasma drug concentration

Capsules

Dosage form

Dipyridamole

Drug

TABLE 6. Application of Amorphous Solid Dispersions in Controlled-Release Technology



BA. Furthermore, the MAD of the drug may also be enhanced, thus reducing the total dose required to elicit the pharmacological response. A stark example of the amorphous form of the drug affecting the BA is that of novobiocin, where only the amorphous form is readily absorbed and is therapeutically active.²⁹¹ BA studies in dogs indicated novobiocin blood levels of 40 mcg/mL upon oral administration of the amorphous form as opposed to undetectable levels for crystalline form. For IM, the glassy and crystalline drugs were reported to be bioinequivalent.²⁹² The fourfold enhancement in dissolution of amorphous vs. crystalline drug was reflected in its higher BA. Most of the time, the amorphous drug is used in the form of solid dispersions as a result of the concerns of physical stability during storage as well as at the time of dissolution in biological environment. The increased rate of drug absorption from solid dispersions has been explained in terms of greater transport rates across the intestinal membranes.²⁹³ Diffusional mass transfer of a drug in steady state, across the intestinal membrane, may be represented as: J = A .Papp (C A − C B ) = Cl (C A − C B )

(27)

where J is flux, A is the effective surface area, Papp is the apparent permeability coefficient, C A and CB are the total drug concentrations at apical and basal sides of the intestinal membrane, respectively, and Cl is the clearance. A greater drug concentration gradient developed at the apical side in the GI lumen will have a direct boosting effect on its flux. If increased solubility of a drug achieved on coprecipitation is due to the formation of a high-energy amorphous phase, then enhancement would be reflected in an increased membrane transport of drug above unit activity. On the other hand, complex formation has been reported to limit the absorption of IM from IM-PEG 6000 coprecipitate, because the complex is too large to cross the intestinal membrane, and drug absorption is dependent upon the dissociation of the complex.²⁹⁴ The flux values of sulfathiazole and hydrocortisone across cellulose membranes were significantly greater from a 5% PVP aqueous solution saturated with the drug/PVP coprecipitates than from solutions saturated with crystalline drugs.²⁹³ This enhanced transit of amorphous drug was also reflected in its thermodynamics, because the ratio of the slopes of amount of drug transferred versus time curves was 3.5:1.0, quite comparable with the 3.8-fold thermodynamic fugacity (or activity) difference between crystalline sulfathiazole and its high-energy amorphous phase. In another study, transport rates of chlorothiazide across everted rat intestinal membranes were also found to be higher from systems supersaturated with drug in the presence of PVP relative to those of crystalline drug.²⁹⁵ This was attributed to the

175


TABLE 7. Comparison of In-Vitro and In-Vivo Advantage with Solid Dispersions BA parameter

Dissolution ratio

Cmax ratio

AUC ratio

Refs.

Mefenamic acid : Egg albumin (1:3)

6.00

2.77

2.13

154

dl-α-Tocopherol : Egg albumin (1:5)

10

1.30

1.15

296

8.00

1.14

1.42

145

200.00

82.00

113.48

297

1.67

2.96

2.50

298

Lonidamine : PVP (1:9)

350.00

1.07

1.74

141

Lonidamine : PEG (1:9)

30.00

1.43

1.43

141

Mebendazole : PVP (1:20)

5.54

5.54

2.78

299

Drug-Carrier System

Albendazole : HPMC : HPMCP (1:5:5) ER-34122* : HPMC (1:1) TAS-301* : Calcium silicate (1:2)

* An investigational drug Drug carrier ratio is given in parentheses HPMC: hydroxypropyl methylcellulose; HPMCP: hydroxypropyl methylcellulose phthalate; PVP: poly(vinyl pyrrolidone); PEG: poly(ethylene glycol)

ability of polymer to retard and/or inhibit drug crystal growth, favoring higher flux of the amorphous form of the drug. The increased rate of drug absorption from amorphous solid dispersions can be reflected in BA, represented in terms of maximal drug plasma level (Cmax), time to reach Cmax (tmax), or the total area under the plasma drug concentration–time curve (AUC). Table 7 gives a comprehensive look over the ratio of amount of drug dissolved in vitro and BA parameters obtained in vivo from amorphous drug/carrier dispersions in comparison to crystalline drug. The in vitro advantage in higher drug dissolution is not reflected in in vivo conditions because of the possible interplay of other biological factors, such as the variation in regional permeability of drug across intestinal membrane, the effect of GI transit time, the precipitation of drug in GI milieu, etc. Polymers added as carriers in solid dispersions continue to play an important role along the GIT by inhibiting drug precipitation and allowing gradual dissolution and absorption of undissolved drug.

1. In Vitro/In Vivo Correlation

In vitro/in vivo correlation (IVIVC) is a mathematical tool for gaining better understanding of drug absorption and its dependence on in vitro release processes.³⁰⁰

176


In the case of amorphous drugs, IVIVC can serve as a predictor of dissolution rate, the controlling factor of drug absorption. Excellent linear correlations were obtained between the amount of reserpine dissolved in 25 minutes from some of the drug/PVP test systems and the cumulative amount of reserpine equivalents excreted in the urine in either 4 or 48 hours.³⁰¹ A linear correlation was found between the amount of nitrofurantoin dissolved in the acidic as well as basic medium after 30 and 90 minutes and the cumulative amount of unchanged drug excreted after 12 hours using solid dispersions of drug in PVP, PEG, or mannitol.³⁰² In the case of mebendazole/PVP complex, for the in vivo parameters related to the amount of absorbed drug (AUC and Cmax), the best correlation was obtained with the in vitro characteristics related to solubility (Cs, Tm, and mean dissolution time).²⁹⁹ Good correlations were also obtained between Tmax, an in vivo parameter related to rate of drug absorption, and log P and log kw´ (kw´ being the capacity factor determined by high-performance liquid chromatography), the in vitro lipophilia/hydrophilia relation parameters.

IV. SUMMARY The changing paradigm of drug discovery has pushed the newer drugs toward higher molecular weight and lipophilicity. Consequently, insoluble drugs have emerged as a dominant category presenting significant challenges to the drug delivery scientists. Amorphization of a drug provides an attractive option for overcoming solubility limitations by use of altered “molecular architecture,” energizing them for rapid solubilization. However, the devitrification of amorphous drugs to their lower energy crystalline counterparts is the most significant challenge for the realization of their true potential. An appreciation of the thermodynamic and molecular level properties such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular level chemical interactions of amorphous drugs is essential for designing customized delivery systems. The engineering of amorphous alloys using specific additives provides an avenue for the stabilization of high solubility amorphous drugs. Understanding the mechanisms of drug release and release modeling will serve in further enhancing the predictability of performance. The enormous success of high-energy amorphous drugs has translated into real in vivo benefits. A thorough understanding of the amorphous systems is the gateway to the predictability of their performance and insight into rational alloy design using carriers. Further work in this field will lead us to delivery systems with customized and predictable performance and a viable option to deliver the “difficult to deliver” insoluble drugs.

177


ACKNOWLEDGMENT Constructive efforts and suggestions from Ms. Garima Chawla are gratefully acknowledged.

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