Stability of Organoleptic Agents in Pharmaceuticals ...

AAPS PharmSciTech ( # 2017) DOI: 10.1208/s12249-017-0866-2

Mini-Review Theme: Stability of Pharmaceutical Excipients Guest Editors: S.Narasimha Murthy and Michael A. Repka

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics Akash Patil,1 Supriya Bhide,1 Mustafa Bookwala,1 Bhavik Soneta,1 Vijaykumar Shankar,1 Ahmed Almotairy,1 Mashan Almutairi,1 and S. Narasimha Murthy1,2,3

Received 25 April 2017; accepted 21 August 2017

Organoleptic agents constitute an important niche in the field of pharmaceutical Abstract. excipients. These agents encompass a range of additives responsible for coloring, flavoring, sweetening, and texturing formulations. All these agents have come to play a significant role in pharmaceuticals and cosmetics due to their ability to increase patient compliance by elevating a formulation’s elegance and esthetics. However, it is essential to review their physical and chemical attributes before use, as organoleptic agents, similar to active pharmaceutical ingredients (APIs), are susceptible to physical and chemical instability leading to degradation. These instabilities can be triggered by API-organoleptic agent interaction, exposure to light, air and oxygen, and changes in pH and temperature. These organoleptic agent instabilities are of serious concern as they affect API and formulation stability, leading to API degradation or the potential for manifestation of toxicity. Hence, it is extremely critical to evaluate and review the physicochemical properties of organoleptic agents before their use in pharmaceuticals and cosmetics. This literature review discusses commonly used organoleptic agents in pharmaceutical and cosmeceutical formulations, their associated instabilities, and probable approaches to overcoming them. KEY WORDS: colors; flavors; sweeteners; textures; stability; interaction.

INTRODUCTION A pharmaceutical formulation is characterized by the presence of one or more active pharmaceutical ingredients (APIs) and additives that are commonly referred as excipients (1). These excipients constitute an important component of a pharmaceutical product; they serve a plethora of purposes such as aiding in the processing of the dosage form during the manufacturing process, protecting or enhancing the stability of the formulation, improving patient compliance, and determining overall product performance in vivo (2,3). Hence, the selection of an appropriate excipient for each pharmaceutical and/ or cosmetic formulation is of paramount importance for its manufacturing and subsequent efficacy.

Akash Patil, Supriya Bhide, Mustafa Bookwala, Bhavik Soneta, Vijaykumar Shankar, Ahmed Almotairy, Mashan Almutairi and S. Narasimha Murthy contributed equally to this work. 1

Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS, USA. 2 Institute for Drug Delivery and Biomedical Research, Bangalore, Karnataka, India. 3 To whom correspondence should be addressed. (e-mail: [email protected])

Among the formulation excipients, organoleptic agents constitute an important and decisive class. The word Borganoleptic^ refers to acting on or involving the use of the sense organs; accordingly, this class of excipients is added to enhance the physical form of the product. This enhancement is usually done by improving the texture, and/ or imparting color, fragrance, and taste to augment the esthetics of the pharmaceutical or cosmetic product. The major goal of the addition of an organoleptic agent is to render the pharmaceutical or cosmeceutical product more appealing to consumers, and thus increase their compliance with dosing regimens and/or their preference for a given cosmetic product (4). To harness the potential of organoleptic agents, it is essential to consider all aspects of the agents in unison and not isolation (4). For example, the coloring agent added should complement the formulation’s taste to ensure greater product compliance; a drug formulation that is red or blue in color would be poorly accepted by the user when combined with a citrus flavoring/odorizing agent, as people normally associate citrus flavors/odors with yellow, green or orange coloring agents. Coloring agents, flavoring agents, sweetening agents, odorizing agents, and texturing agents are the most widely used organoleptic agents in pharmaceutical/cosmetic preparations. Coloring agents, as the name suggests, are organoleptic agents 1530-9932/17/0000-0001/0 # 2017 American Association of Pharmaceutical Scientists

Patil et al. employed to impart color to the pharmaceutical and cosmeceutical products. They can further be classified into natural or synthetic coloring types (5). Natural coloring is obtained from natural sources such as minerals, plants, and/or animals. Mineral colors, also known as pigments, are used in cosmetics or in formulations that are used externally. Common examples include red ferrous oxide, yellow ferrous oxide, carbon black, among others. Coloring agents that are extracted from plants are also called pigments, and include chlorophyll, saffron, and indigo from the indigo plant for green, yellow, and blue coloring, respectively (5). Colors obtained from animal sources are limited and commonly include tyrian purple obtained from snail secretions, and bright red obtained from cochineal insects. Synthetic coloring types include agents obtained after processing chemicals, such as azo, nitroso, or nitro (5). Flavoring agents are used in both pharmaceutical and cosmeceutical products for imparting salty, sour, bitter, and sweet flavors to the formulation. Flavoring agents are used for both pharmaceutical and cosmetic products. The selection of the flavoring agent depends on the taste of API and on the age of the patient for which the pharmaceutical product is intended (6). For example, most children prefer sweet fruity tastes, unlike adults. Sweetening agents are generally used in pharmaceutical formulations to make them palatable to the patient. In some cases, they are also used as taste masking agents. They can be further classified into natural sweeteners (e.g., sucrose, sorbitol) and artificial sweeteners (e.g., aspartame, saccharin) (6,7). Odorizing agents are used to provide a pleasant odor to both pharmaceutical and cosmetic products. These agents are generally obtained by processing and extracting essential oils from an animal (e.g., musk) or plant source (e.g., vanillin, citral, furanone) (8–10). Texturing agents are used in both pharmaceutical and cosmetic products; however, they find greater application in cosmetic products to improve and enhance the texture, feel, and flow of liquid cosmetic products such as creams, lotions, and ointments. When utilizing organoleptic agents in pharmaceutical and cosmeceutical products, it is important to evaluate their stability profiles, as they could potentially affect the physical, chemical, and microbial integrity of the formulation (11). Hence, stability testing for organoleptic agents is performed to provide evidence that organoleptic excipients remain stable and do not deteriorate or show any instability over the product’s shelf life (12). Factors that affect stability include storage conditions such as temperature, pH, oxygen, moisture, and light. Stability guidelines for assessing organoleptic instability and maintaining the stability of pharmaceutical products are outlined by the International Conference on Harmonization (ICH) in section Q1. This review discusses the instabilities associated with organoleptic agents, approaches to overcome these issues, and provides a brief a review of the guidelines for performing stability studies for organoleptic excipients and pharmaceutical products. COLORING AGENTS Coloring agents find vast applications in pharmaceutical and cosmeceutical products. The United States of America Food and Drug Administration (US FDA) defines these coloring agents as Bany dye, pigment, or other substance that can impart color to a food, drug, or cosmetic or to the human body^ (12). Esthetic and/or technical objectives are the two

major underlying principles for the use of coloring agents. Coloring agents are also colloquially referred as Bcosmetics for pharmaceutical preparations,^ because of the fact that they can be used to manipulate the esthetic appearance of a pharmaceutical/cosmeceutical product (13). One of the fundamental functions of coloring agents is to improve patient acceptance of a pharmaceutical product. For example, brightly colored formulations such as cherry red cough syrup are more likely to be used by the pediatric population as they are attractive and appealing when compared to uncolored formulations (14). Imparting a distinguishing appearance to the pharmaceutical dosage form is also a vital task that is accomplished by the addition of a coloring agent. They serve as an easy way to help patients and physicians identify and differentiate between dosage forms; for example, the anesthetic trichloroethylene, is colored blue to distinguish it from chloroform, because of their physical resemblance (15). Coloring agents also aid in protecting photolabile constituents in the formulation; for example, insoluble colors or pigments such as iron oxides, titanium oxide, and some aluminum lakes provide stability to lightsensitive active materials in tablet or capsule formulations (16). Color additives can make pharmaceutical products attractive, appealing, appetizing, and informative, and hence find a myriad of applications in many dosage forms, including tablets (either the tablet-core or tablet-coating), hard or soft gelatin capsules (in the capsule shell), oral liquids, topical creams, toothpastes, ointments, and salves (13,17). All the coloring agents that are used in pharmaceutical and/or cosmeceutical formulations should possess certain prerequisite properties. They should be physiologically inert and nontoxic, remain stable during storage, be compatible with the active ingredient and other excipients in the formulation, be readily available and inexpensive, and be free from foul odor and/or unusual taste (13). All the coloring agents used in pharmaceutical/cosmeceutical formulations must be approved and certified by Food Drug and Administration (FDA) and Food Drug and Cosmetics (FD&C) Act. Accordingly, the federal FD&C Act defines three categories of coloring agents: (1) FD&C colors, certifiable for use in coloring foods, drugs, and cosmetics (e.g., FD&C Red No. 3 [erythrosine], FD&C Red No. 40 [allura Red AC], FD&C Blue No. 2 [indigo carmine]); (2) D&C colors, dyes and pigments considered safe in drugs and cosmetics when in contact with mucous membranes or when ingested; (3) Ext. D&C colors, colorants that, because of their oral toxicity, are not certifiable for use in ingestible products but are considered safe for use in externally applied products (17,18). The use and addition of coloring agents is governed by the following regulations: (1) colors are food additives under the 1958 FD&C Act; (2) all color additives require premarket approval via the color petition process; (3) colors are listed in the US Code of Federal Regulations, Part 21, Section 73 and 74 (19). Table I lists the various FD&C approved coloring agents with their instabilities and potential approaches to overcoming their instabilities. SWEETENING AGENTS Sweetening agents are added to pharmaceutical preparations primarily to enhance the palatability of the product

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics Table I. Stability Issues Associated with Commonly Used Coloring Agents and Approaches to Overcoming Them

Coloring agents

Instability

Approaches to overcome instability

Betalains (betaxanthins + betacyanins) Natural colorant (U.S FDA 21 CFR section – 73.40 EEC No. – E 162) Food (N-heterocyclic in nature and derived from plants) (20)

• Temperature-dependent degradation if optimal pH conditions are maintained. • Degradation is correlated with color fading or browning due to subsequent polymerization (21).

Turmeric (curcumin +2 demethoxylated curcuminoids) Natural colorant (U.S FDA 21 CFR section – 73.600 EEC No. – E 100) Food (phenolic compounds that impart yellow color) (24) Anthocyanin Natural colorant (U.S FDA 21 CFR section – 73.169 EEC NO. – E 163) Food (phenolic compounds responsible for red, blue, and purple colors) (27) Beta-carotene Natural colorant (U.S FDA 21 CFR section – 73.1095) Drugs (isoterpenoid that imparts red-orange colors) (28) Indigo carmine (FD&C Blue No. 2) Synthetic colorant (U.S FDA 21 CFR section – 74.1102) Drugs (organic salt derived from indigo, responsible for blue color) (30)

• Photo degradation by U.V. and visible radiation in dry and liquid preparations. • pH instability leading to color changes from yellow to brownish red/deep red (25).

• Complex formation: betalain-EDTA complex stabilizes the color. • Co-pigmentation with flavanols to form adducts such as pyranoanthocyanins, pyranoanthocyanin-phenols, pyranoanthocyanin-flavanols to maintain color intensity (22). • Stabilizers such as ascorbic acid, isoascorbic acid, and citric acid to protect the colorant from oxygen degradation. • Encapsulation yields dry and stable colorants. Guar gum and pectin are commonly used for encapsulation (23). • Curcuminoids complexation with water-soluble branched or cyclic polysaccharides or water-dispersible proteins leads to a photo-stabilized colorant. • Optimal pH should be 3–7, maintained with buffering agents (26).

Allura Red AC (FD&C Red 40) Synthetic colorant (U.S FDA 21 CFR section – 74.1340) Drugs

• Stability of the color is influenced by pH, temperature, presence of enzymes, light, and the presence of complexing compounds such as metals, phenolic acids, and flavonoids.

• Avoid light and store under dark conditions to prevent photo-instability. • Acylated anthocyanins are more stable when compared to non-acylated anthocyanins. • Refrigerate preparations containing anthocyanins. • Anthocyanins are complexed with catechins (phenol) to obtain structural stability.

• Decomposition due to changes in pH, temperature, light, and metal ions. • Oxidative degradation leading to a loss in color intensity.

• Use antioxidants such as ascorbic acid or tocopherols to reduce the rate of oxidation. • Use metal-sequestering agents such as EDTA or citric acid for stabilization (29).

• Highly susceptible to oxidation by ultraviolet light, resulting in rapid fading. • Unstable at pH 7–8. • Unstable after exposure to heat and light. • Very poor stability in the presence of acid, base, and sulfur dioxide (31). • Fades more rapidly in the presence of sugars (dextrose, mannitol, sucrose, lactose, and sorbitol) and certain non-ionic surfactants (32). • Contains an azo linkage, which can be broken by ascorbic acid, leading to the fading of color. • Prolonged exposure to heat breaks the azo linkage. • Iron reduces azo dyes-Allura Red AC.

• Encapsulation generally improves the agent’s pH, light, and heat stability.

• Encapsulating of the colorant with a suitable polymer helps overcome heat, light, and pH instabilities. • Use complexing agents to capture iron impurities. • Use antimicrobial agents to protect the reduction of azo dye by microbes (34).

Patil et al. Table I. (continued) Coloring agents (azo dye that imparts dark red color) (33) Chlorophyll Natural colorant Cu-chlorophyll complex (U.S FDA 21 CFR section – 73.1125) Drugs (naturally occurring chlorin pigment in plants that impart green color) (35) Titanium dioxide Synthetic colorant (U.S FDA 21 CFR section –73.1575) Drugs (oxide of titanium that imparts white color) (37) Iron oxide Synthetic colorant (U.S FDA 21 CFR section –73.1200) Cosmetics (imparts shades of red color) (39) Caramel natural colorant (U.S FDA 21 CFR section –73.1085) Drugs (beige to dark brown color obtained by heating sugars) (40) Annatto (bixin + norbixin + monomethyl ester of dicarboxylic carotenoid compound) Natural colorant (U.S FDA 21 CFR section – 73.1030) Drugs (carotenoid derivative that imparts yellow-orange color) (41) Erythrosine Synthetic colorant (FD&C Red no. 3) (U.S FDA 21 CFR section –74.1303) Drugs (organic compound derived from iodine that imparts a cherry-pink color) (43)

Instability • Microorganisms reduce azo dyes (microbial instability). • Intensity of green color is highly dependent on pH (36). • Decomposition by oxidation. • Light is a major contributor to instability.

Approaches to overcome instability

• Reduction in the oxygen content of titanium oxide in presence of light. This oxygen can easily recombine again as a part of a reversible photochemical reaction, particularly if there is no oxidizable material available, leading to significant changes in the optical and electrical properties of the pigment. • Renders hard gelatin capsules brittle at higher temperatures when the residual moisture is 11–12%.

• Storage in a well-closed container in a cool and dry place. • Avoid light (38).

• Possible precipitation due to interactions with the proteins present in the formulation. This occurs when the color and protein are oppositely charged. • Interaction with calcium ions to form insoluble complexes.

• Different charges of color are available so that the color can be chosen according to the charge of the system as determined by protein content. • Effective water filtration and use of chelating agent (EDTA) to remove calcium ions from the system (34). • Ascorbyl palmitate (10%) is an effective antioxidant. • Use demineralized water or demineralized glucose syrup with 0.5% ascorbic acid to prevent fading. • Use cloudifiers (e.g., bees wax and natural gums) to minimize fading (42).

• Light is the most destructive. • Fades in the presence of metal ions.

• Precipitation is observed below pH 4. • Highly susceptible to light, leading to fading of color.

(44). They find wide application in oral formulations such as solutions, suspensions, syrups, tablets, chewable oral formulations, etc. and in all the dosage forms intended for the pediatric population (45). They may be used to mask the obnoxious taste of the API and/or of any other excipient and

• Make a dispersion using stabilizers and emulsifiers. • Symbiotic use of antioxidants (e.g., tocopherol and ascorbyl palmitate) to enhance stability. • Encapsulation to prevent instability.

• Store in well-closed containers in a cool and dry place (38).

• Maintain the pH above 4 with buffering agents. • Techniques such as encapsulation to stabilize the colorant (34).

to ensure better patient compliance in the pediatric population. The commonly used sweetening agents are broadly classified into natural and artificial sweeteners. Natural sweeteners such as sucrose and dextrose are the most

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics Table II. Stability Issues Associated with Commonly Used Sweetening Agents and Approaches to Overcoming Them

Sweetening agents

Instability

Approaches to overcome the instability

Alitame (38)

• Degradation at elevated temperatures or when in solution at low pH. • Can degrade in a one-step process to aspartic acid and alanine amide (under harsh conditions) or in a slow two-step process by first degrading to its b-aspartic isomer and then to aspartic acid and alanine amide. • Excessive heating can cause a reduction in pH and caramelization of solutions. • Interaction with amines, amides, amino acids, peptides, and proteins in the aldehyde form. • Brown discoloration and decomposition occur with strong alkalis. • May cause browning of tablets containing amines (Maillard reaction). • Hygroscopic and absorbs significant amounts of moisture at a relative humidity greater than 60%. • With strong acids or alkalis, forms a brown discoloration. • May cause browning of tablets containing amines.

• Store in a well-closed container in a cool and dry place. • Avoid contact with oxidizing and reducing substances or strong acids and bases.

Dextrose (38)

Fructose (38)

Neotame (38)

• Changes in pH, moisture, and temperature may lead to decomposition.

Saccharine sodium (38) Xylitol (38)

• Decomposes at high temperatures (125°C) at a low pH (pH 2) for over 1 hour. • Marginally hygroscopic. • Caramelization can occur only if it is heated for several minutes near its boiling point. • Caramelizes at elevated temperatures. • Unstable below pH 3. • Hygroscopic with instability due to changes in moisture and humidity. • Incompatible with alkaline earth hydroxides, as they react with sucrose to form sucrates. • Caramelizes and decomposes above 160°C. • In aqueous solution, at highly acidic conditions (pH < 3), and at high temperatures (≤ 35°C), it is hydrolyzed to a limited extent, producing 4-chloro-4deoxygalactose and 1,6-dichloro-1,6-dideoxyfructose. • Decomposes when heated at elevated temperatures into carbon dioxide, carbon monoxide, and minor amounts of hydrogen chloride. • Interaction with the coloring agent iron oxide, leading to discoloration. • Addition of liquid polyethylene glycols to a sorbitol solution, with vigorous agitation, produces a waxy, water-soluble gel with a melting point of 35–40°C. • Less stable at some specific temperatures, especially when it is subjected to long-term processing under high temperature and pH in solution media.

Tagatose (38) Confectioner’s sugar (38)

Sucralose (38)

Sorbitol (38)

Aspartame (46)

Acesulfame potassium (47)

Rebaudioside A (48)

• May undergo decomposition on exposure to temperatures more than 40°C for a period of time. • pH-dependent instability. • Less stable in aqueous media with pH below 2.0. • Unstable at high temperatures.

• Store in a well-closed container in a cool, dry place. • Avoid contact with oxidizing and reducing substances, or strong acids and bases.

• Store in its original sealed packaging at temperatures below 25°C and a relative humidity of less than 60%. • Maintain pH between 3–4 and temperature between 4–70°C for aqueous solutions. • Store bulk material in a well-closed container, in a cool, dry place. • Stable for up to 5 years at room temperature. • Maintain pH between 3–4 and temperature between 4–70°C for aqueous solutions. • Avoid use of oxidizing agents. • Store in a well-closed container in a cool, dry place. • Store at room temperature. • Maintain pH greater than 3. • Store in a well-closed container in a cool and dry place.

• Store in a well-closed container in a cool, dry place, at a temperature not exceeding 21°C.

• Store in glass, plastic, aluminum, and stainless steel containers. • Store in an airtight container in a cool and dry place. • Store in solid form for relatively better stability. • Maintain pH at 3.0–5.0. • Avoid high temperatures, and temperatures less than 100°C. • Preferred storage temperature is 30°C. • Maintain pH values between 3–3.5 • Maintain pH values between 4 and 8. • Very stable at temperatures of 25°C.

Patil et al. Table III. Flavors Imparting Specific Tastes (49)

Taste

Flavor

Acid Salty Alkaline Sweet

Citrus flavors (orange, lime) Butterscotch, maple Vanilla, custard Fruity flavors (berry, apple, honey)

commonly used sugars for sweetening agents. Various other monosaccharides such as sorbitol, mannitol, and xylitol are also used as non-calorific sweeteners in patients with diabetes mellitus. Solvents such as glycerol also find an application as sweetening agents in oral liquid formulations (44). Artificial sweeteners such as saccharin, cyclamate, and aspartame are the most commonly used sweetening agents. They are not metabolized in the body and are excreted unchanged in urine. The calorific content of artificial sweeteners is insignificant and the intensity of sweetness provided by artificial sweetening is higher than natural sweetening agents; for example, saccharin is 500 times sweeter than sucrose (44,45). The sweeteners could be either used in their solid crystalline/amorphous form or in their liquid form. Generally, the sweetening agents are preferred in their liquid forms, because they get dissolved in saliva to give the immediate sweet taste (44). Sucrose syrup is the most commonly available and utilized sweetening agent due to its good taste, mouthfeel, aftertaste, and its low economic cost. But it has tendency to get crystallized out; hence, to avoid instability it is combined with other sweetening agents like sorbitol, glycerin etc. (44). The abovementioned sucrose syrup is one such example of the instabilities associated with sweetening agents. Table II further enumerates the natural and artificial sweetening agents, with their associated instabilities and possible approaches to overcoming them. FLAVORING AGENTS Flavoring agents are one of the commonly used pharmaceutical excipients to increase the esthetic value of a pharmaceutical formulation to improve patient compliance and palatability (6). Flavoring agents are organoleptic agents that impart an intended characteristic flavor to a formulation, with a simultaneous enhancement in the odor of the dosage form. The flavoring agents commonly used as pharmaceutical aids are either natural in origin or artificially synthesized. These flavoring agents are used in a plethora of pharmaceutical dosage forms such as tablets, syrups, emulsions, suspensions, and other oral dosage forms (8). They are mainly utilized to mask the unpleasant odor or taste of the formulation without causing physical and chemical incompatibility (8). The use of a specific flavoring agent depends on various factors such as the nature of the API, the intended dosage formulation, the target population, etc. (6). Table III shows commonly used flavors used to impart specific tastes. For example, citrus flavors such as orange or lime are often used in conjunction with antihistamines such as diphenhydramine and promethazine (50). Minty flavors are often used in

antacid formulations; fruity flavors and minty flavors in dosage forms are intended for the pediatric and geriatric populations, respectively (51). Children and pediatric population have always been a target population that has necessitated the need for the addition of a flavoring agent. Pediatric population has sensitive sensory systems for detecting tastes and smells, and if the tastes and smells do not suit their palatability, they immediately reject it (52). Adding pleasant flavor volatiles such as bubble gum or other fruity and candy flavors may help induce children to consume a medicine. Sometimes, flavoring agents such as vanillin also find application in masking undesirable off-flavors developed during storage by products susceptible to oxidative degradation (53). In addition to the flavors listed above, there are a myriad range of flavors that are used in pharmaceutical dosage forms, which are elaborated in Table III. All the routinely used flavoring agents are equally susceptible to degradation and stability issues, like an API. Because the degradation or instability of a flavoring agent could potentially render the dosage form unpalatable, it is essential to take into consideration potential stability issues associated with flavoring agents before use to attempt to overcome or avoid them. Table IV further elaborates on these issues. TEXTURING AGENTS Texturing agents are chemical substances that are added to pharmaceuticals to improve their texture and appearance and provide a pleasant mouthfeel. They are widely used in cosmetics as well to improve their sensorial characteristics, specifically their texture and feel. Texturing agents impart pharmaceuticals and cosmetics with creaminess, clarity, thickness, viscosity, and various other characteristics, to enhance their elegance and esthetics. The texturing agents, in addition to the other organoleptic agents, also play a decisive role improving patient compliance (76). Various texturing agents are available commercially for both pharmaceutical and cosmeceutical use. They are added in pharmaceutical dosage forms such as syrups, emulsions, lozenges, suppositories, etc., and in cosmetic products like lipsticks, creams, lacquers, lotions, etc. (76). The texturing agents can be of natural origin, such as polysaccharide gums, or synthetically prepared. They may be used alone (e.g., coconut oil) or in a blend (e.g., Glyceryl dibehenate/ Compritol 888™), to provide an acceptable texture to the ultimate product (77,78). They also aid in providing a stable pharmaceutical or cosmeceutical structure to the product, thereby increasing its shelf life. The texturing agents mainly consist of emulsifiers and coemulsifiers, thickening agents, stabilizers, and gelling agents (79). All these agents serve varying purposes, including imparting a desired viscosity and texture, solubilizing the other organoleptic agents (e.g., emulsifiers and co-emulsifiers are used for solubilizing coloring and flavoring agents), and improving the stability of the product (79). The texturing agents that are used in pharmaceutical or cosmeceutical products are generally long-chain fatty acid lipoid and/or glyceride derivatives (79). Due to their lipoidal chemical structure, they are susceptible to various degradation processes mediated by light, chemicals, enzymes, pH

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics Table IV. Stability Issues Associated with Commonly Used Flavoring Agents and Approaches to Overcoming Them

Flavoring agent(s)

Active component for flavor

Instability

Approaches to overcome the instability

Orange, lime, lemon, lemon tea, and lemongrass flavors

Citral (49,54–59)

• α, β-unsaturated aldehyde, and thus highly susceptible to acid catalyzed cyclization and oxidative degradation, particularly in the presence of light and heat. • Leads to an off-flavor.

Vanilla flavor

Vanillin (60–64)

• Incorporation of antioxidants (BHT, BHA, n-propyl gallate, α-tocopherol, nordihydroguaiaretic acid, and n-tritriacontane). • Incorporation of plant extracts including grape seed, pomegranate seed, green tea, and black tea (presence of phenolics prevents oxidative degradation). • Use of ubiquinone–coenzyme Q, an important nutraceutical, to prevent degradation. • Use of vanillin propylene glycol acetal instead of vanillin, as it has greater stability than the vanillin parent. • Use of antioxidants to prevent oxidative degradation.

• Three reactive functional groups: aldehydic group, phenolic hydroxyl, and aromatic nucleus. • Undergoes oxidative degradation, and accelerated oxidative degradation at higher temperatures. • Reacts chemically with proteins, which reduces the intensity of the flavor. Caramel, Furanone derivatives: • Instability in presence of air and in strawberry, furaneol, norfuraneol, aqueous solutions. raspberry, homofuraneol (65–68) • pH-dependent stability as changes grape, mango, and in pH lead to tautomerization. pineapple flavors • Highly susceptible to thermal degradation (> 130°C). • Undergoes photo-oxidation due to ring-opening after a free radical attack. Maple flavor M alt o l an d f u ran o n e • Reacts with metal ions (e.g., iron) to form derivatives (69,70) metal complexes that affect flavor. Apricot flavor (70) • Intensely creamy and can easily undergo phase separation. • Incompatible with acidic APIs or excipients. Cinnamon flavor

Butterscotch

Coriander, sweet basil, and lavender. Peach

Mint flavors (peppermint and spearmint)

• Temperature sensitive, and at higher temperatures (> 70°C), it undergoes degradation to produce benzaldehyde, leading to a change in flavor and odor. Diacetyl (72) • Susceptible to oxidation, leading to changes in the flavor (the flavor becomes intensely sweet). • Tends to form a separate phase. Linalool (73) • Undergoes auto oxidation to form hydroperoxides, which are common contact allergens. Gamma-decalactone (74) • Instable in presence of oxidizing agents and bases, which cause opening of the lactone ring. Menthol, terpenoids, and • Polymerization of the menthofuran (75) active constituents leading to an increase in the viscosity of the flavor (minor pathway). • Oxidation of menthofuran leading to the production of an off-odor. Cinnamaldehyde (71)

• Stabilize using chelating agents and antioxidants. • Use only in formulations where the pH is expected to be acidic. • During formulation, it should be a constituent of the lipophilic phase. • Stabilize with chelating agents. • Usually used with peach flavor as the lactones aid in stabilizing its creamy taste and texture. • Usually compounded with non-acidic excipients/APIs. • Monitor temperature during the compounding of the flavor in the dosage form.

• Incorporation of antioxidants. • Thickening agents (e.g. alginates and gums) to maintain viscosity and prevent phase separation. • Use antioxidants and/or purge with inert gas in the formulation. • Use antioxidants to prevent oxidation. • Maintain pH in the acidic range. • Use antioxidants to prevent oxidation of menthofuran. • Reduce the menthofuran content in the peppermint flavor during distillation.

Patil et al. Table V. Stability Issues Associated with Commonly Used Texturing Agents and Approaches to Overcoming Them

Agent

Instability

Approaches at overcoming the instability

Coconut oil (77)

• Oxidative degradation. • Free radical reactions leading to rancidity.

Glyceryl dibehenate (Compritol 888) (78)

• Polymorphism into less stable forms (majority sub-α) with inferior emolliency.

Phospholipids and lecithin (80,81)

• Oxidative degradation. • Degradation in presence of iron and copper ions • Free radical-mediated autoxidation.

Polysaccharides: cellulose derivatives, dextran, alginates, and gums (guar and xanthan gum) (82)

• Interaction with proteins in the formulation to form insoluble complexes, affecting the viscosity and phase of the product. • Interaction with metal ions to undergo a change in their consistency. • Instability with changes in pH.

Cocoa butter (83)

• Coalescence of cocoa butter in products forms hardened agglomerates or formation of polymorphs, affecting the texture of the product due to partial melting and/or inefficient shear during mixing during the cocoa butter phase.

Polyethylene glycol derivatives (84,85)

• Degradation in presence of light, high temperatures, and atmospheric oxygen to form carboxylic acid and ester derivatives.

Propylene glycol and derivatives (86)

• Oxidative degradation in presence of air. • Hygroscopic, with a change in weight in presence of water and an increase in their ability to undergo microbial degradation. • Acceleration of degradation by UV light and metal contaminants. • Higher temperatures during formulation act as catalysts for oxidative degradation. • Rancidification leading to an off-odor and color. • Oxidative degradation.

• Marketed as a butylated glycol cocoa, which is chemically inert to oxidative degradation and rancidification • Addition of chelating agents and antioxidants. • Maintain temperatures below 70°C during formulation to prevent polymorphism • Store at room temperature. • Use of co-emulsifiers (e.g., PEG, acetylated monoglycerides, Span, Tweens). • Use of antioxidants and chelating agents • Keep the products in tightly closed containers. • If proteins are to be used, then their concentration should be as minimal as possible. • Use of a chelating agent. • Avoid extreme changes in temperature and pH. • Use co-emulsifiers to improve the stability and texture of the product. • Adopt uniform and controlled temperature cycles during the formulation of cocoa butter products. • Efficient mixing at optimal speed. • Store in well-closed containers at room temperature. • Store in tightly capped opaque containers. • Purge with argon gas to drive out oxygen and prevent oxidative degradation. • Maintain lower temperatures during formulation, as high temperatures could accelerate the oxidative degradation. • Store in well-closed and opaque containers, away from light and moisture. • Addition of antioxidants and chelating agents. • Maintain temperatures below 40°C during the formulation procedures.

Glycerides (87,88)

• Esterification as caprylic and capric acid derivatives to improve oxidative stability. • Inter-esterification and use as a blend of different glycerides.

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics changes, and radiations. Therefore, to overcome any potential degradation of the texturing agents and/or pharmaceutical and cosmeceutical product containing them, it is essential to review the utility versus stability profile of the texturing agents; to formulate the most optimum product with the most superior esthetics without compromising on the stability of the product. Table V outlines the various texturing agents, their instabilities, and potential ways of overcoming them. DRUG-ORGANOLEPTIC AGENT INCOMPATIBILITIES One of the major contributors to the instability of the organoleptic agents is the interaction of the drug and organoleptic agent to concomitantly react and elicit degradation reactions (89–92). Some organoleptic agents are known to potentiate the degradation of the API, leading to instability of the complete pharmaceutical/cosmeceutical product. These incompatibilities could be due to physical or chemical interactions between the two components of the formulation (92). Thus, it is of utmost importance that a careful evaluation of the organoleptic excipients be performed before their consideration as a potential additive. In particular, the assessment should include the stability of the individual organoleptic agent and its probable interactions with the API. Coloring agents are known to interact to with certain APIs; hence, some colors are contraindicated when a certain API is to be used in the pharmaceutical formulation. The FD&C blue no.1 coloring agent is known to interact with certain drugs such as sulfathiazole, phenobarbital, thymol, and sulfaguanidine, and significantly affect the dissolution rate of its containing tablets (89). FD&C red no.3 (coloring pigment: erythrosine) is usually contraindicated in the manufacturing of gelatin capsules or formulations containing gelatin because it affects the disintegration of the gelatin, and in some cases alters the physical nature of the gelatin matrix (90). Riboflavin is known to interact with FD&C red no.22 color, resulting in retardation of the disintegration and dissolution of riboflavin tablets (91). Sweetening agents have also been found to interact with APIs, causing incompatibilities that may affect the performance of a given pharmaceutical dosage. Lactose is incompatible with acyclovir, ketoprofen, metformin, amlodipine, lisinopril, fluconazole, primaquine, promethazine, fluoxetine, aminophylline, and ranitidine. Hence, the use of lactose as a sweetening agent is limited in these situations (92). In the case of flavoring agents, the prevalence of API and flavoring agent interactions leading to instability is also unfortunately high. Ethyl vanillin, a flavoring agent, reacts with neomycin sulfate (antibiotic) or succinyl sulfathiazole (antibacterial sulfonamide), resulting in a color change in the formulation, yellow discoloration (93). Mint oils (active flavoring agent: menthol) are incompatible with chloral hydrate formulations (an anti-anxiety pharmaceutical) and other flavoring agents containing thymol as the principle flavoring component, as it degrades the API and potentially causes instability in the formulation (93). When using the texturing agents, care should be taken in the selection process as they also could potentially react with the API, leading to formulation instability, degradation, and a

probable loss in activity. For example, PEG is known to have multiple interactions with APIs, affecting various facets of the formulation. PEG interacts with penicillins and leads to a decrease in antibacterial activity. PEG also reduces the antimicrobial activity of parabens in cosmetics and interacts with salicylic and tannic acids, leading to a change in the physical nature of the cosmeceutical product (i.e., a decrease in the viscosity of the product) (93). PEG has also been reported to react physically with APIs such as sulfonamides, leading to their discoloration, and with sorbitol (a sweetening agent) to cause its precipitation, thereby negatively affecting the overall integrity of the pharmaceutical formulation (93). Hence, a careful review and evaluation of any potential or anticipated incompatibilities between an API and organoleptic agent is essential to maintain pharmaceutical/ cosmeceutical stability. STABILITY GUIDELINES Organoleptic stability studies utilize historical data including that found in the literature to generate a report summarizing the data and draw conclusions about organoleptic stability. The organoleptic should be stable at product stability testing conditions, which are selected based on the physical and chemical characteristics of the drug or substance, and the expected changes that might appear during storage of the products. Validated analytical procedures should be used for product stability testing, and the testing should evaluate the microbiological characteristics, preservative loss, physical and organoleptic properties, and chemical and biological stability. The stability testing of organoleptic agents are carried out as per the ICH Q1A(R2) guidelines or the International Pharmaceutical Excipients Council (IPEC) excipient stability testing guidelines (11,77). Excipient stability studies in accordance with ICH Q1A(R2) guidelines are conducted on excipients in commercial packages located in temperature monitored warehouses (94). The IPEC classifies the excipients as being either very stable, stable, or of limited stability. The very stable excipients should be stable during the manufacturing process and demonstrate stability for at least 5 years in the stated packaging conditions; their stability should also be predictable based on excipient properties, physical and chemical. Stable excipients are more susceptible to changes as compared to the very stable excipients during the manufacturing or packaging of products. The stable excipients should have a retest period after 2–5 years. In contrast, the limited stability excipients have less than 2 years during their retest interval or expiration date. Both the stable and limited stability excipients should have historical data supporting the given retest interval or expiration date and stability indicating characteristics (12). Generally, stability testing of products are carried out as per the guidelines of the ICH harmonized tripartite guideline for BStability testing of new drug substances and products,^ Q1A(R2) or World Health Organization, WHO Technical Report Series, No. 953, 2009, BStability testing of active pharmaceutical ingredients and finished pharmaceutical products.^ (94). When the pharmaceutical/cosmeceutical products fail stability testing guidelines, approval is usually withdrawn and they are usually recalled from the market.

Patil et al. CONCLUSION

13.

Organoleptic agents are an important class of excipients in the formulation of pharmaceutical/cosmeceutical products, as they impart an esthetic attribute to the product. Organoleptic agents such as colors, flavors, and sweeteners play an important role in improving patient compliance, whereas other organoleptic agents such as texturing agents aid in maintaining the overall stability of the pharmaceutical/ cosmeceutical products. A careful evaluation of the organoleptic agents for stability is imperative, as they, along with the API and other excipients, contribute in maintaining the integrity and stability of the finished product. This conclusion can be corroborated based on the aforementioned discussion on the instabilities of organoleptic agents. It is of vital importance to evaluate and assess an organoleptic agent for its physical, chemical, and microbiological stability to design a stable pharmaceutical/cosmeceutical product with enhanced elegance to ensure greater patient acceptability.

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15. 16.

17.

18. 19.

20. 21.

REFERENCES

1.

2. 3. 4.

5. 6. 7.

8.

9.

10.

11. 12.

US Pharmacopeia [Internet]. US Pharmacopeia, Excipients. 2007 [cited 2016 Oct 20]. 1–11 p. Available from: http:// w w w. u s p . o r g / s i t e s / d e f a u l t / fi l e s / u s p _ p d f / E N / U S P N F / chapter3.pdf Jacobs MG, Klug DB, Moreton RC, Silverstein I. Qualification of excipients for use in pharmaceuticals. Chim Oggi. 2009;27(5 Suppl):11–3. Loftsson T. Excipient pharmacokinetics and profiling. Int J Pharm [Internet]. 2015 Mar 1 [cited 2017 may 4];480(1–2):48–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25596414. Mohanta G, Parimalakrishnan S, Manna P. An overview of organoleptic excipients [Internet]. Pharmabiz.com. 2011. p. 1–6. Av a i l a b l e f r o m : h t t p : / / w w w. p h a r m a b i z . c o m / NewsDetails.aspx?aid=65654&sid=21 Gennaro AR. Remington: the science and practice of pharmacy. 21st ed. Lippincott Williams and Wilkins:1060 p. Weerawatanakorn M, Wu J, Pan M, Ho C. Reactivity and stability of selected flavor compounds. J Food Drug Anal. 2015. p. 176–90. Lenik J, Wesoły M, Ciosek P, Wróblewski W. Evaluation of taste masking effect of diclofenac using sweeteners and cyclodextrin by a potentiometric electronic tongue. J Electroanal Chem [Internet]. 2016 [cited 2017 May 4];780:153– 9 Available from: http://www.sciencedirect.com/science/article/ pii/S1572665716304751 Allen L, Popovich N, Ansel H. Pharmaceutical dosage forms and drug delivery systems [internet]. 9th ed. Allen L, Popovich N, Ansel H, editors. Pharmaceutical dosage forms and drug delivery systems. MD and PA: Lippincott Williams & Wilkins; 2011. 130 p. Available from: http://pharmachitchat.com/wpcontent/uploads/2015/05/ansel-drug-delivery-system.pdf Classen C, Howes D, Synnott A. Aroma: the cultural history of smell [Internet]. 18th ed. London and New York: Routledge; 1994. 1–20 p. Available from: file:///C:/Users/akash/Downloads/ 1440494494.Constan Classen, David Howes, Anthony Synnott Aroma The Cultural History of Smell 1994.pdf. US patent for odor-masking coating for a pharmaceutical preparation Patent (Patent # 6,667,059 issued December 23, 2003) - Justia Patents Search [Internet]. Available from: http:// patents.justia.com/patent/6667059 US Pharmacopeia USP29-NF 24. 2006. 2994 p. The IPEC Excipient stability program guide [Internet]. International Pharmaceutical Excipients Council 2010 p. 1–14. Av a i l a b l e f r o m : h t t p : / / i p e c - e u r o p e . o rg / U P L O A D S / 100311_IPECStabilityGuide-Final.pdf

22.

23. 24.

25. 26. 27.

28.

29.

30.

31. 32.

33.

Allam K, Kumar G. Colorants—the cosmetics for the pharmaceutical dosage forms. Int J Pharm Pharm Sci. 2011. p. 13–21. Schoneker D. Coloring Agents for use in pharmaceuticals. In: Swarbrick J, editor. Encylopedia of Pharmaceutical Technology [Internet]. 3rd ed. New York: Informa Healthcare; 2007. p. 648. Av a i l a b l e f r o m : h t t p : / / w w w. g m p u a . c o m / P r o c e s s / EncyclopediaPT.pdf Peck B. Pharmaceutical dosage forms—tablets. 2nd ed. 116–117 p. Rowe RC. The opacity of tablet film coatings. J Pharm Pharmacol [Internet]. 1984 Sep [cited 2016 Oct 20];36(9):569– 72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 6149277. Kanekar H, Khale A. Coloring agents: current regulatory perspective for coloring agents intended for pharmaceutical and cosmetic use. Int J Pharm Phytopharm Res. 2014;3(5):365– 73. US Pharmacopeia USP39-NF 34. 2016. US FDA. Summary of color additives for use in the United States in foods, drugs, cosmetics, and medical devices. [Internet]. Center for Food Safety and Applied Nutrition; [cited 2016 Oct 20] Available from: http://www.fda.gov/forindustry/ coloradditivhttps://www.fda.gov/forindustry/coloradditives/ coloradditiveinventories/ucm115641.htm#table3A Azeredo H. Betalains: properties, sources, applications, and stability—a review. Int J Food Sci Technol. 2009;44:2365–7. Stintzing F, Carle R. Betalains—emerging prospects for food scientists. Trends Food Sci Technol. 2007;18(10):514–25. Trouillas P, Sancho-García J, De Freitas V, Gierschner J, Otyepka M, Dangles O. Stabilizing and modulating color by copigmentation: insights from theory and experiment. Chem Rev. 2016;116(9):4937–82. Khan M. Stabilization of betalains: a review. Food Chemistry. 2016. p. 1280–5. Menon V, Sudheer A. Antioxidant and anti-inflammatory properties of curcumin [Internet]. Advances in Experimental Medicine and Biology. Boston, MA: Springer US; 2007 [cited 2016 Nov 3]. p. 105–25. Available from: http://link.springer.com/ 10.1007/978-0-387-46401-5_3 Maing I, Miller I. Curcumin-metal color complexes [Internet]. US; US 4263333 A, 1979 [cited 2016 Oct 20]. Available from: https://www.google.com/patents/US4263333 Lauro G, Francis J. Natural food colorants—science and technology. 1st ed. New York: Marcel Dekker; 2000. p. 205–23. He J, Giusti MM. Anthocyanins: Natural colorants with health-promoting properties. Annu Rev Food Sci Technol [Internet]. 2010 Apr [cited 2016 Nov 3];1(1):163–87 Available f r o m : h t t p : / / w w w. a n n u a l r e v i e w s . o r g / d o i / 1 0 . 1 1 4 6 / annurev.food.080708.100754 Francis F. Carotenoids as food colorants [Internet]. Cereal Foods World. 2000 [cited 2016 Nov 3]. p. 198–203. Available f r o m : h t t p : / / w w w. t a n d f o n l i n e . c o m / d o i / f u l l / 1 0 . 1 0 8 0 / 10408398209527357 Frank J. Beta carotene: a work-horse colorant & pro-vitamin A [ i n t e r n e t ] . P R O 2 0 1 5 . Av a i l a b l e f r o m : h t t p : / / knowledge.ulprospector.com/2838/fbn-beta-carotene-workhorse-colorant-pro-vitamin-a/ Peica N, Kiefer W. Characterization of indigo carmine with surface-enhanced resonance Raman spectroscopy (SERRS) using silver colloids and island films, and theoretical calculations. J Raman Spectrosc [Internet]. 2008 Jan [cited 2016 Nov 3];39(1):47–60 Available from: http://doi.wiley.com/ 10.1002/jrs.1813 Thorngate J. Synthetic food colorants, food additives. In: Thorngate J, Salminen S, Branen L, Davidson M, editors. Food Additives. 2nd ed. Marcel Dekker; 2002. p. 477–500. Anderson M, Opawale F, Rao D, Delmarre D, Anyarambhatla G. Excipients for oral liquid formulations. In: Katdare A, Chaubal M, editors. Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems [Internet]. New York London: Informa Healthcare USA, Inc; 2006 [cited 2016 Oct 20]. p. 174. Available from: http://www.crcnetbase.com/doi/ book/10.1201/9781420004137 Abramsson-Zetterberg L, Ilbäck NG. The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo. Food Chem

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics Toxicol [Internet]. 2013 Sep [cited 2016 Nov 3];59:86–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23748052. 34. Knehr E. Maintaining color stability [internet]. Natura Products Insider, Informa Health. 2006. p. 1–4. Available from: http:// www.naturalproductsinsider.com/articles/2006/08/maintainingcolor-stability.aspx# 35. Humphrey AM. Chlorophyll. Food Chem Elsevier. 1980;5(1):57–67. 36. Özkan G, Ersus Bilek S. Enzyme-assisted extraction of stabilized chlorophyll from spinach. Food Chem [Internet]. 2015 Jun 1 [cited 2016 Oct 20];176:152–7. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/25624218. 37. Periasamy V, Athinarayanan J, Al-Hadi A, Juhaimi F, Mahmoud M, Alshatwi A. Identification of titanium dioxide nanoparticles in food products: induce intracellular oxidative stress mediated by TNF and CYP1A genes in human lung fibroblast cells. Environ Toxicol Pharmacol. 2015;39(1):176–86. 38. Rowe R, Sheskey P, Quinn M. Handbook of pharmaceutical excipients [internet]. 6th ed. Rowe R, Sheskey P, Quinn M, editors. Pharmaceutical press. London Chicago: APhA/ Pharmaceutical Press.; 2009. Available from: http:// www.pharmpress.com/product/9780857110275/excipients 39. Cornell R, Schwertmann U. Introduction to the iron oxides. In: Cornell R, Schwertmann U, editors. The iron oxides: structure, properties, reactions, occurrences and uses. 2nd ed. Wiley VCH; 2004. p. 1–7. 40. Sengar G, Sharma H. Food caramels: a review [internet]. Journal of food science and technology. Springer; 2012 [cited 2 01 6 No v 3] . p . 16 86 –9 6 . Av ai l a b l e fr o m : h t t p : / / www.ncbi.nlm.nih.gov/pubmed/25190825. 41. Hagiwara A, Imai N, Ichihara T, Sano M, Tamano S, Aoki H, et al. A thirteen-week oral toxicity study of annatto extract (norbixin), a natural food color extracted from the seed coat of annatto (Bixa orellana L.), in Sprague-Dawley rats. Food Chem Toxicol [Internet]. 2003 Aug [cited 2016 Nov 3];41(8):1157–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 12842184. 42. Britton J. Carotenoids. In: Houghton J, Henry G, editors. Natural Food Colorants. 1996. p. 197–243. 43. Lyday P. Iodine and iodine compounds. Wiley VCH: Ullmann’s Encyclopedia of Industrial Chemistry; 2005. 44. Pawar S, Kumar A. Issues in the formulation of drugs for oral use in children: role of excipients. Paediatr Drugs [Internet]. 2002 [cited 2016 Oct 20];4(6):371–9. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/12038873. 45. Basu D, Sen D. Organoleptic agents: adaptability, acceptability and palatability in formulations to make it lucrative. World J Pharm Pharm Sci. 2015;4(10):1573–86. 46. Graves D, Luo S. Decomposition of aspartame caused by heat in the acidified and dried state. J Agric Food Chem [Internet]. American Chemical Society; 1987 May [cited 2016 Oct 20];35(3):439–42 Available from: http://pubs.acs.org/doi/ abs/10.1021/jf00075a038 47. Klug C, Lipinski G. Sweeteners and sugar alternatives in food technology. 2nd ed. O’Donnell K, Kearsley M, editors. West Sussex, UK: Wiley Blackwell; 2012. 93–112 p. 48. Prakash I, DuBois G, Clos J, Wilkens K, Fosdick L. Development of rebiana, a natural, non-caloric sweetener. Food Chem Toxicol [Internet]. 2008 Jul [cited 2017 may 17];46(7):S75–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18554769. 49. Sharma V, Sharma P. Flavouring agents in pharmaceutical formulations. Anc Sci Life [Internet]. 1988 [cited 2016 Oct 20];8(1):38–40 Available from: http://www.pubmedcentral. nih.gov/articlerender.fcgi?artid=3331350&tool=pmcentrez& rendertype=abstract 50. Sedrak M, Patel D. Drugs used in the treatment of common disorders of the gastrointestinal system. In: Tindall W, Sedrak M, Boltri J, editors. Patient-centered pharmacology: learning system for the conscientious prescribe. Philadelphia: FA Davis; 2013. p. 177–96. 51. Hoffman A, Salgado R, Dresler C, Faller R, Bartlett C. Flavour preferences in youth versus adults: a review. Tob Control. 2016;25:ii32–9. 52. Mennella J, Beauchamp G. Optimizing oral medications for children. Clin Ther [Internet]. NIH Public Access; 2008 Nov

53. 54.

55.

56. 57.

58.

59.

60.

61.

62.

63.

64. 65.

66. 67.

68.

69.

[cited 2017 may 17];30(11):2120–32. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/19108800. Burri J, Graf M, Lambelet P, Löliger J. Vanillin: more than a flavouring agent—a potent antioxidant. J Sci Food Agric. 1989;48:49–56. Schieberle P, Grosch W. Identification of potent flavor compounds formed in an aqueous lemon oil/citric acid emulsion. J Agric Food Chem [Internet]. American Chemical Society; 1988 Jul [cited 2016 Oct 20];36(4):797–800 Available from: http:// pubs.acs.org/doi/abs/10.1021/jf00082a031 Kimura K, Iwata I, Nishimura H. Relationship between acidcatalyzed cyclization of citral and deterioration of lemon flavor. Agric Biol Chem [Internet]. 1982 May 9 [cited 2016 O c t 2 0 ] ; 4 6 ( 5 ) : 1 3 8 7 – 9 Av a i l a b l e f r o m : h t t p : / / www.tandfonline.com/doi/full/10.1080/00021369.1982.10865253 Iwanami Y, Tateba H, Kodama N, Kishino K. Changes of lemon flavor components in an aqueous solution during UV irradiation. J Agric Food Chem Am Chem Soc. 1997;8561(96):463–6. Rouseff R, Naim M. Citrus flavor stability. Flavor Chem [Internet]. 2000 Mar 23 [cited 2016 Oct 20];756(3):101–21 Available from: http://pubs.acs.org/doi/abs/10.1021/bk-20000756.ch008 Freeburg E, Mistry B, Reineccius G. Stability of citralcontaining and citralless lemon oils in flavor emulsions and beverages. Perfum Flavorist [Internet]. 1994;19:23–32. Available from: http://www.perfumerflavorist.com/flavor/application/citrus/Stability-of-Citral-Containing-and-Citralless-Lemon-Oils-inF l a v o r - E m u l s i o n s - a n d - B e v e r a g e s 370512591.html#sthash.BRCIOdHl.dpuf Choi S, Decker E, Henson L, Popplewell L, McClements D. Influence of droplet charge on the chemical stability of citral in oil-in-water emulsions. J Food Sci [Internet]. Blackwell Publishing Inc; 2010 Aug [cited 2016 Oct 20];75(6):C536–40 Available from: http://doi.wiley.com/10.1111/j.1750-3841.2010.01693.x Mishra P. Kinetics and mechanisms of oxidation of 4hydroxy -3-methoxy benzaldehyde (vanillin) by bi (V) in aqueous alkaline medium. Int J PharmTech Res. 2009;1(4):1234–40. Mourtzinos I, Konteles S, Kalogeropoulos N, Karathanos V. Thermal oxidation of vanillin affects its antioxidant and antimicrobial properties. Food Chem. 2009;114(3):791–7. Li Z, Grun I, Fernando L. Interaction of vanillin with soy and dairy proteins in aqueous model systems: a thermodynamic study. J Food Sci [Internet]. Blackwell Publishing Ltd; 2000 Sep [cited 2016 Oct 20];65(6):997–1001 Available from: http:// doi.wiley.com/10.1111/j.1365-2621.2000.tb09406.x Mcneill V, Schmidt K. Vanillin interaction with milk protein isolates in sweetened drinks. J Food Sci [Internet]. Blackwell Publishing Ltd; 1993 Sep [cited 2016 Oct 20];58(5):1142–7 Available from: ht tp://doi.wiley.com /10.1111/j.13652621.1993.tb06133.x Kenya I, Takashi A. Vanillin acetals. US. 2012;8236970:B2. Roscher R, Schwab W, Schreier P. Stability of naturally occurring 2,5-dimethyl-4-hydroxy-3[2H]-furanone derivatives. Food Res Technol [Internet]. Springer-Verlag; 1997 Jun 10 [cited 2016 Oct 20];204(6):438–41 Available from: http:// link.springer.com/10.1007/s002170050109 Chen C, Shu C, Ho C. Photosensitized oxidative reaction of 2,5Dimethyl-4-hydroxy-3(2H)-furanone. J Agric Food Chem Am Chem Soc. 1996;44(8):2361–5. El Hadi M, Zhang F, Wu F, Zhou C, Tao J. Advances in fruit aroma volatile research [internet]. Molecules. 2013 [cited 2016 O c t 2 0 ] . p . 8 2 0 0 – 2 9 . Av a i l a b l e f r o m : h t t p : / / www.ncbi.nlm.nih.gov/pubmed/23852166. Shu C, Mookherjee B, Ho C. Volatile components of the thermal degradation of 2,5-Dimethyl-4-hydroxy-3(2H)furanone. J Agric Food Chem [Internet]. American Chemical Society; 1985 May [cited 2016 Oct 20];33(3):446 Available from: http://pubs.acs.org/doi/abs/10.1021/jf00063a030 Antipova I, Mukha S, Medvedeva S. Determination of composition and instability constants of maltol complexes with iron(III) ions. Russ Chem Bull [Internet]. Kluwer Academic Publishers-Plenum Publishers; 2004 Apr [cited 2016 Oct 20];53(4):780–4 Available from: http://link.springer.com/ 10.1023/B:RUCB.0000037841.67079.2b

Patil et al. Rovira D. Dictionary of flavors. 3rd ed. John Wiley & Sons; 2008. 113–114. p. 71. Gholivand M, Ahmadi F. Simultaneous determination of transcinnamaldehyde and benzaldehyde in different real samples by differential pulse polarography and study of heat stability of trans-cinnamaldehyde. Anal Lett [Internet]. Taylor & Francis Group; 2008 Dec 10 [cited 2016 Oct 20];41(18):3324–41 Available from: http://www.tandfonline.com/doi/abs/10.1080/ 00032710802507893 72. Gilmore L. Process for preparing a caramel butterscotch flavor syrup. US 4753814 A, 1987. 73. Bäcktorp C, Wass J, Panas I, Sköld M, Börje A, Nyman G. Theoretical investigation of linalool oxidation. J Phys Chem A Am Chem Soc. 2006;110(44):12204–12. 74. MSDS - W236012 [Internet]. Available from: http:// www.sigmaaldrich.com/MSDS/MSDS/DisplayMSDSPage.do? country=US&language=en&productNumber=W236012& brand=ALDRICH&PageToGoToURL=http%3A%2F%2Fw w w. s i g m a a l d r i c h . c o m % 2 F c a t a l o g % 2 F p r o d u c t % 2 Faldrich%2Fw236012%3Flang%3Den 75. Reitsema R, Frederick J. Oxidation of peppermint oil. Ind Eng Chem. 1952;44:176–80. 76. Marketsandmarkets.com. Food texture market by applications, functionalities & geography - 2018 [Internet]. 2013. Available from: http://www.marketsandmarkets.com/Market-Reports/ texturizing-agents-market-1224.html 77. Diamante C. Cosmetic Ingredient Review 2008;1–31. 78. Becker K, Salar-Behzadi S, Zimmer A. Solvent-free melting techniques for the preparation of lipid-based solid oral formulations. Pharm Res [Internet]. 2015 May [cited 2016 O c t 2 0 ] ; 3 2 ( 5 ) : 1 5 1 9 – 4 5 . Av a i l a b l e f r o m : h t t p : / / www.ncbi.nlm.nih.gov/pubmed/25788447. 79. Texturizers and emulsifiers. https://www.gattefosse.com/cosmetic-texturizers-emulsifiers. 80. Porter N, Wolf R, Weenen H. The free radical oxidation of polyunsaturated lecithins. Lipids [Internet]. Springer-Verlag; 1980 Mar [cited 2016 Oct 20];15(3):163–7 Available from: http://link.springer.com/10.1007/BF02540963 81. Pichot R, Watson R, Norton I. Phospholipids at the interface: current trends and challenges. Int J Mol Sci [Internet]. Multidisciplinary Digital Publishing Institute; 2013 Jun 3 [cited 2016 Oct 20];14(6):11767–94 Available from: http:// www.mdpi.com/1422-0067/14/6/11767/ 82. Ghosh A, Bandyopadhyay P. Polysaccharide-protein interactions and their relevance in food colloids. In: Karunaratne D, editor. The Complex World of Polysaccharides [Internet]. 2012 [cited 2016 Oct 20]. Available from: https://doi.org/10.5772/ 50561 70.

83.

Leal-Calderon F. Emulsified lipids: formulation and control of end-use properties. Oléagineux, Corps gras, Lipides [Internet]. John Libbey Eurotext; 2012 Mar 15 [cited 2016 Oct 20];19(2):111–9 Available from: http://www.ocl-journal.org/ 10.1051/ocl.2012.0438 84. Votano J, Parham M, Hall L. PEG stability: a look at pH and conductivity changes over time in polyethylene glycols. Chem… [ I n t e r n e t ] . 2 0 0 4 ; 5 7 7 – 8 2 . Av a i l a b l e f r o m : h t t p : / / onlinelibrary.wiley.com/doi/10.1002/cbdv.200490137/abstract 85. Glastrup J. Degradation of polyethylene glycol. A study of the reaction mechanism in a model molecule: tetraethylene glycol. Polym Degrad Stab Elsevier. 1996;52(3):217–22. 86. Propylene glycol stability and storage [Internet]. D o w C h e m i c a l s . c o m . 20 1 6. Ava i l a b l e f r o m : h t t p :/ / dowac.custhelp.com/app/answers/detail/a_id/7485/~/propyleneglycols—stability-%26-storage 87. Neobee® Medium chain triglycerides brochure, Stepan Lipid Nutrition Pharmaceutical. 2012. 88. Lipocire™ A SG [Internet]. Available from: http:// www.gattefosse.com/en/products/lipocire-a-sg.html?textureskys,texturizing-specialties-kh6. 89. Piccolo J, Tawashi R, Saad HY, Higuchi WI, Buckley HE, Ives MB, et al. Inhibited dissolution of drug crystals by a certified water-soluble dye. J Pharm Sci [Internet]. Elsevier; 1970 Jan [cited 2016 Nov 3];59(1):56–9. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/5411326. 90. Cooper J, Ansel H, Cadwallader D. Liquid and solid solution interactions of primary certified colorants with pharmaceutical gelatins. J Pharm Sci [Internet]. Wiley Subscription Services, Inc., A Wiley Company; 1973 Jul [cited 2016 Nov 3];62(7):1156– 64 Available from: http://linkinghub.elsevier.com/retrieve/pii/ S0022354915411359 91. Prillig E. Effect of colorants on the solubility of modified cellulose polymers. J Pharm Sci [Internet]. Wiley Subscription Services, Inc., A Wiley Company; 1969 Oct [cited 2016 N o v 3 ] ; 5 8 ( 1 0 ) : 1 2 4 5 – 9 Av a i l a b l e f r o m : h t t p : / / linkinghub.elsevier.com/retrieve/pii/S0022354915370271 92. Bharate S, Bharate S, Bajaj A. Incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review. J Excipients Food Chem. 2010;1(3):3–26. 93. Excipient guide [Internet]. Available from: http:// www.excipientsguide.com/excipient_details.aspx?Id=151 94. US FDA. Guidance for industry Q1A(R2) stability testing of new drug substances and products. ICH [Internet]. 2003 [cited 2016 Oct 20];(November):1–22 Available from: http:// www.fda.gov/cder/guidance/index.htm