EDUCATION PRACTICE UPDATE

Excipient selection for compounded

First published in the Australian Journal of Pharmacy, pharmaceutical capsules: Vol. 98, No.1164, August 2017, pp.78-83. Reproduced and distributed by the Medisca group of they’re only fillers, right? companies with the permission of the publisher.

▲ Patricia Ullmann, compounding pharmacist

Excipients are not merely inert fillers and, in contrast, AFTER COMPLETING THIS ACTIVITY, THE LEARNER may affect bioavailability to the extent of causing SHOULD BE ABLE TO: significant patient harm. • describe types of excipients used in powder-filled oral compounded capsules; • describe factors to consider when choosing excipients for capsule formulations; Function of excipients in • bioavailability of compounded • explain the significance of the Biopharmaceutical pharmaceutical formulations formulation compared to the Classification System (BCS) of active Pharmaceutical excipients offer commercial formulation, pertinent pharmaceutical ingredients and its relevance to the compatibility for the specific needs in cases when the compounding selection of excipients; of the patient, as they address patient rationale is to address proprietary • understand factors to consider when compounding adherence. They also have a significant drug shortages; slow-release capsules. role in maintaining stability of the active • physical, chemical and microbial pharmaceutical ingredient (API) over stability of the overall formulation; The 2010 Competency Standards addressed by this time, such as protecting the API from • desired onset of action, duration of activity include (but may not be limited to): 5.1, 5.2 degradation. Essentially, excipients action and therapeutic intent; and The 2016 Competency Standards addressed by this function to regulate or balance the • patient-specific allergies and activity include (but may not be limited to): 3.4 electrochemical and physical properties intolerances. of the dosage form thus contributing to the creation of environments that affect Types of excipients used in stability, solubility, permeation and powder-filled oral compounded absorption. Excipients are functional capsules ingredients that facilitate the therapeutic This article will focus on excipients function of the API, not just inert specific to oral compounded capsules, Accreditation Number: A1708AJP1 ingredients in a formulation. particularly diluents. Far more than being This activity has been accredited for 1.0 hour of Group One Factors compounding pharmacists ‘just a filler’, an appropriately chosen CPD (or 1.0 CPD credit) suitable for inclusion in an individual pharmacist’s CPD plan which can be converted to 1.0 hour of must consider when selecting the most diluent, in an appropriate concentration, Group Two CPD (or 2.0 CPD credits) upon successful completion appropriate excipients1 include the: can alter the bioavailability of active of relevant assessment activities. • stability of the active ingredient, such pharmaceutical ingredient, influencing Accreditation expires: 01/08/2019 as hygroscopicity, oxidation, hydrolysis; whether a drug dose is: • physical properties of the active • within the therapeutic window; ingredient, such as the powder • below it, in which case efficacy is by found to contain the labelled amount flowability, suspendability, colour, definition unachievable; or of phenytoin, which confirmed that the flavour, smell and texture; • above it, in which case adverse events correct amount of active was included in • pH of solubility and pH of stability are more likely and toxicity may occur. the manufacturing process. of the active ingredient within In addition, the investigation the formulation base, for aqueous A dramatic example where a change determined that: solutions and suspensions; in the capsule excipient blend altered • all the affected patients had received • solubility of the active ingredient in efficacy, is given by Lloyd Allen.2 A the same brand of 100mg phenytoin the biological environment in which it change in the excipients in a phenytoin capsules; is to be delivered; formulation of a commercially • the new formulation had replaced • potential interaction between the API manufactured product in the 1960s calcium sulfate with lactose; and and excipients; in Australia lead to cases of toxicity. • the new formulation had slightly • potential interaction between the Following the cases of toxicity, the increased amounts of magnesium excipient and the intended packaging; capsules’ potency was analysed and silicate and magnesium stearate.

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Considering the solubilities of the excipients for which the amounts were TABLE 1: TYPES OF EXCIPIENTS AND THE REASONS FOR THEIR USE IN CAPSULES significantly altered: • calcium sulfate is listed as “slightly EXCIPIENT TYPE REASONS FOR USE soluble in water”; Diluent Fill empty space; increase accuracy • lactose is listed as “freely soluble in water”. Glidant Reduces a powder’s adherence to plastics

Since the API phenytoin (the active) Electrostatic neutralizer Reduce electrical charge; prevents running up metal is “freely soluble in water”, the lactose (excipient filler) would serve to increase Adsorbent To reduce or prevent two chemicals from undergoing sorption the “wetting” of the active, thereby Reduces powders from sticking to surfaces and/or to itself enhancing the dissolution of the active, Flow agent which consequently lead to increased Slow-release agent Retards the bioavailability of active agent absorption and the systemic toxicity in patients. This was confirmed when the Chelating agent Binds to and neutralizes trace metals production of the capsule returned to the previous formula containing the calcium Antioxidant Prevents oxidation sulfate instead of lactose, as the patients’ serum levels returned to normal. Tracer Dye Quality assurance measure; visible test This example demonstrates that excipients are not merely inert fillers and, in contrast, may affect bioavailability to the TABLE 2: SPECIFIC EXCIPIENTS AND THEIR RESPECTIVE FUNCTION IN extent of causing significant patient harm. POWDER-FILLED CAPSULES Table 1 identifies types of excipients and the reasons for their use in capsules. FUNCTION EXCIPIENT Table 2 lists specific excipients and their respective function in powder-fill capsules. Adsorbent Bentonite When selecting only one excipient as the filler, such as the commonly used Diluent Acidophilus microcrystalline cellulose, the potential Diluent Calcium carbonate beneficial attributes of other excipients are foregone. Lactose monohydrate, Diluent Lactose, anhydrous which is also a commonly used filler in compounding, exhibits poor flowability Diluent Lactose monohydrate and interacts with various drug actives.3 In contrast, a considered combination of Diluent Mannitol excipients ameliorates the formulation. An ideal capsule powder blend for Diluent; Adsorbent Magnesium carbonate compounded capsules may have the Diluent Magnesium oxide following properties: • lactose-free to accommodate patient- Diluent Microcrystalline cellulose specific intolerance; • gluten-free to accommodate patient- Diluent Sorbitol specific intolerance; • neutralise electrostatic repulsion of Diluent Starch highly static APIs; Diluent; Glidant Talc • increase chemical stability; • increase drug dissolution; Diluent Tapioca powder • assist with disintegration, if necessary; • provide bulk; and Flow agent Sodium bicarbonate • increase compounding efficiency. Glidant Magnesium stearate Selecting excipients for compounded capsules Neutralise electrostatic repulsion Silica gel using biopharmaceutical classification system Neutralise electrostatic repulsion Sodium lauryl sulphate In 1995, Amidon et al introduced the Slow-release agent Hydroxypropyl methylcellulose concept of the Biopharmaceutical

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When compounding capsules, selecting an excipient powder CLASS I: CLASS II: High solubility Low solubility blend that provides protection High permeability High permeability of the active ingredient(s) from degradation is the first priority.

handling and packaging of the active(s) Permeability CLASS III: CLASS IV: and the compounded preparation. If the active is hygroscopic,

(human intestinal absorption) intestinal (human High solubility Low solubility protecting it from degradation due to hygroscopicity is the priority, for Low permeability Low permeability which specific powder blends are available or may be developed. For non-hygroscopic APIs, the blend should be based on the solubility of the drug Solubility: Volume (ml) of water required to at the prescribed dose in a volume of dissolve the highets dose strengh over pH 1–8 range 250mL. A compounding pharmacist should choose a blend based on the considerations shown in Figure 2.10 The Dose Number concept developed FIGURE 1: THE FOUR CLASSES OF THE BIOPHARMACEUTICAL by Amidon assists in understanding CLASSIFICATION SYSTEM whether the drug has a high solubility or low solubility considering the dose and the Classification System (BCS).4 The BCS hence ingredients need to aid dissolution volume of fluid with which it will be taken. was developed as a means to provide a and act as wetting and disintegrating According to Ferreira in 2008, to scientific approach for drug classification agents. Class III medications require determine the Dose Number, use based on aqueous solubility and absorption-enhancing excipients. the equation:11 intestinal permeability. For instance, Class IV medications may have serious a drug is considered highly permeable bioavailability obstacles, requiring when the extent of absorption in humans absorption-enhancing excipients.6 Dose Number = Highest Usual Dose (mg) ÷ 250mL is more than 90% and highly soluble The BCS provides an insight into Solubility of API (mg/mL) when the highest dose is soluble in properties of active pharmaceutical 250mL or less of buffer, ranging between ingredients and consequently the Do = Mo ÷ Vo a pH of 1 and 7.5. properties of the excipients required So Hence, the BCS covers the three in formulations. The BCS is used by main factors which govern the rate and the pharmaceutical industry to select Where: Do is the Dose Number the extent of drug absorption from excipients for manufactured immediate Vo is the volume of water with which the 7,8,9 immediate release solid oral dosage forms release capsule and tablet products. dose should be taken (250 mL) (e.g. tablets, capsules). These factors are: It may be used by compounding So is the aqueous solubility of drug (refer to • dissolution rate; pharmacists such as when compounding Merck Index, Martindale). • solubility; and immediate-release capsules. To address • permeability.5 the needs of each biopharmaceutical class, a blend containing different Where Do is <1, use an excipient blend suitable for highly soluble actives.* The four classes of the BCS shown in excipients could be used in the Where Do is >1, use an excipient blend suitable for poorly soluble actives.* Figure 1 are Class I, Class II, Class III compounded formula. * Solubility concept according to BCS developed by Amidon, not according to API solubility.3 and Class IV. When compounding capsules, Class I medications normally have few selecting an excipient powder blend bioavailability challenges; hence suitable that provides protection of the active Pharmacists may refer to the BP excipient blends need to offer flowability ingredient(s) from degradation is Solubilities Table10 in order to convert and disintegration without impeding the first priority. Oxidation and light word definitions of solubility, into dissolution. Class II medications are sensitivity may be managed when numerical values, which can be inserted limited in their absorption capabilities; considering choice of storage, the into the above equation.

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Hygroscopic/ Active Pharmaceutical Ingredient Deliquescent Eutectic mixture High Solubility* Low

Class I and III ** Class II and IV **

CapsuBlend – H CapsuBlend – S CapsuBlend – P

Excipient to Select another OK No Yes API Interaction compatible excipient

*Volume (mL) of water required to dissolve the highest dose strength over pH 1–8 range. **Biopharmaceutical Classification System.

FIGURE 2: FLOWCHART FOR SELECTION OF PREMIXED EXCIPIENTS FOR ORAL COMPOUNDED CAPSULES10

Melatonin capsule example Naltrexone capsule example LoxOra is a powder blend to improve in the BCS in the BCS the dissolution of actives and reduce Melatonin 5mg capsules, 1 nocte. Naltrexone capsules 3mg, 1 daily, static12 developed by PCCA. This one Melatonin is slightly soluble in water solubility 100mg/mL; hygroscopic active excipient blend is designed to be used in and not hygroscopic. The BP Solubilities any oral capsule formulation and with table defines slightly soluble as “from most APIs according to PCCA. Number of Doses = Usual Dose ÷ 250mL 100 to 1000 parts”. Meaning solubility ranges from 1000mg/100mL to Solubility of API (mg/mL) Compounding slow-release 1000mg/1000mL. In the worst case capsules scenario, solubility is 1000mg/1000mL, Do = 3mg ÷ 250mL = 0.00012 Compounding pharmacists are often which equates to 1mg/mL. asked to compound hard gelatin 100mg/mL This example emphasises that BCS capsules with a slow-release component considers more than the aqueous in order to improve patient adherence solubility of the drug. Although melatonin Irrespective of solubility, since it is a hygroscopic API 6 use the and pharmacotherapy.13,14 This kind is slightly soluble in the water, the DO excipient blend suitable for hygroscopic actives. of preparation is suitable for APIs that number is <1, which classifies it as a highly require frequent dosing within a 24-hour soluble active.* The reason being, that period due to their short half-life.3,6 A considering a volume of 250 mL of water There are a number of proprietary consequential benefit when compounding and a very low therapeutic dose, this drug pre-mixed excipient blends on the slow-release oral capsules is the advantage is highly soluble as per Amidon’s concept. market. The Capsublend range, of minimising a high peak blood level that developed by Medisca is based on the is sometimes associated with untoward BCS to meet the specific requirements effects. “The onset is a little slower and Number of Doses = Usual Dose ÷ 250mL of drugs within BCS classes.11 The the release is a little prolonged, but not Solubility of API (mg/mL) range contains various combinations of within narrowly defined limits. This aids glidants, diluents, electrostatic repulsion in patient adherence and is one aspect of Do = 5mg ÷ 250mL = 0.02 neutralisers and disintegrants in three pharmaceutical care.”15 different excipient blends: There are a number of terms that 1mg/mL 1. Capsublend-H, for hygroscopic drugs should not be used for compounded 2. Capsublend-P, for drugs identified as formulations as the terms have specific Since Do <1, use excipient powder blend suitable for highly poorly soluble in the BCS by Amidon definitions in the pharmaceutical soluble actives.* 3. Capsublend-S, for drugs identified as industry and the United States highly soluble in the BCS by Amidon. Pharmacopoeia, which could imply that

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from cellulose17,19 used to retard release of CH compounded APIs. It is enzyme resistant 3 and stable over a pH range of 3–11. CH3 H H H O HPMC is considered a stable non-toxic, O H O CH HO OH non-irritating material, widely used in HO 2 O H HO H the pharmaceutical industry, compatible H H H H with most APIs apart from some O oxidizing agents.18 It is non-ionic, and HO O HO CH thereby has minimal interaction with 2 O O CH2 H H O H O acidic, basic, or electrolytic systems, and CH3CHCH2 is suitable with soluble and insoluble CH2CHCH3 CH drugs at high and low concentrations. O n-2 3 OH HPMS provides the release of a drug in a CH3 controlled manner, effectively increasing the duration of release of a drug to prolong its therapeutic effect.17 FIGURE 1: TYPICAL CHEMICAL STRUCTURE OF HYDROXYPROPYL METHYLCELLULOSE The solution viscosities of celluloses (HPMC)13 are given in millipascal-seconds (mPa.s) measured at 2% concentration in water the compounded preparation is the same contact with an aqueous medium, a at 20°C. The viscosity of an aqueous as the commercially available product. strong viscous gel is formed.16 The gel solution of the Methocel cellulose These terms are as follows:13 layer formed within capsules tends to be ethers, products of Dow Chemicals, is 1. Controlled release weaker than that provided in tablets due proportional to the molecular weight 2. Delayed release to the low compaction of the contents. or chain length of the specific Methocel 3. Extended release The dissolution rate and API delivery is product used. Methocel cellulose ethers 4. Long acting then determined by the diffusion of the are available in various viscosity grades, 5. Modified release API through this gel layer. ranging from 3mPa.s to 20,000mPa.s. 6. Prolonged action Drug solubility is a very important For example, Methocel E4M is a HPMC, 7. Sustained action factor which needs careful consideration which is commonly used in slow-release 8. Sustained release on a case-by-case basis. Different drug compounded capsules, has a viscosity 9. Targeted release characteristics, such as high or low 4000 mPa.s; while Methocel E10M is a solubility, affect gel characteristics and HPMC with a viscosity of 10,000 mPa.s. Unless there are supportive studies, drug release. High-solubility drugs can The concentration of the cellulose also only the term ‘Slow Release’ may be dissolve by diffusing through the gel determines the viscosity of the solution. used on labels of extemporaneously matrices and this is considered to be the Although some researchers report wider prepared capsules designed to release main pathway for their release. However, ranges in the order of 10% w/w to 80% slowly. In the absence of bioavailability release also occurs through erosion w/w,18 there is much evidence that 30% studies and clinical research giving rise of the gel matrix. It is said that highly w/w to 40% w/w of specific types of to a plasma-drug concentration profile, soluble drugs also act as pore formers hydroxypropylmethylcellulose result in the claims attributed to a compounded with the formation of micro-cavities and reliable and consistent drug systems.13,17,20 delivery system need be conservative. In make the gel structure more porous and Two slow-release extemporaneously the context of pharmacy compounding weaker, hence leading to increased drug compounded niacinamide capsule where there is an absence of appropriate release rates.17 preparations containing 40% and 60% experimental testing procedures, the base In order to slow the release of active v/v hypromellose respectively, were used with a compounded dosage form drugs, compounding pharmacists studied in comparison to an immediate (composed of the excipients) should not prepare capsules that contain a mixture release proprietary product. The release be thought of as having the status of that of the API and specific celluloses at a rates were 80% of the API released at 6 developed by a research laboratory. set percentage and a secondary diluent hours, 7 hours and less than 20 minutes Under no circumstances can a such as microcrystalline cellulose,13 compounded medication be labelled which is not known to affect the release with the proprietary name of the original rate. Trituration, geometric dilution brand, as the pharmacokinetic features and uniformity in the preparatory Drug solubility is a very cannot be assumed to be the same. procedures are required. Quality Moreover, intellectual property laws abide, compounding also requires validation important factor which needs aside from misleading representations. and quality assurance measures. The mechanism which slows drug Hydroxypropylmethylcellulose careful consideration on a release relies on the powder mixture (HPMC), more commonly known forming a hydrophilic gel system. When as hypromellose,18 is a water soluble, case‑by-case basis. the slow-release polymer comes into hydrophilic, non-ionic polymer derived

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PRACTICE UPDATE 2 Excipient selection for compounded pharmaceutical capsules: they’re only fillers, right? CPD CREDITS This unit attracts up to 2 Group Two CPD credits. Accreditation number: A1708AJP1. Accreditation expires: 01/08/2019. GROUP TWO Each question has only one CORRECT answer.

1. Select the TRUE statement regarding B The taste and smell of the API. C Ranges of 10% w/v to 80% w/v the Biopharmaceutical Classification C The BCS class that the specific dose of have been used. System (BCS): the API falls into. D NONE of the above statements A The BSC is used by the pharmaceutical D All of the above are FALSE. industry and compounding pharmacies in consultation with the FDA. 3. Which excipients are commonly used 5. Identify the TRUE statement(s) B The BSC categorises APIs according in pharmaceutical compounding to below in relation to the claims to their dissolution rate, solubility and slow the release of the active in an oral which can be made in relation to permeability at its highest dose in compounded capsule dosage form? compounded capsules with impaired 250mL of buffer. A Hydroxypropylmethylcellulose release properties. C According to the BSC, an API which is B Microcrystalline cellulose A Pharmacists may use the term “control highly insoluble in water will always C Methocel E4M release” in reference to capsules that require excipients to improve its D A and C have been compounded with polymers bioavailability. E All of the above that retard the release of the API. D Excipient selection is unimportant B Pharmacists may make a definitive when considering the electromagnetic 4. Identify the FALSE statement(s) below claim about the duration of action of properties of an API. in relation to the amount of the excipient the slow-release formulation based on intended to slow the release of an API in first principles. 2. When determining the choice of excipients compounded capsules. C Pharmacists may use the trade name for a capsule which of the following factors A The amount varies depending on the of a slow-release drug compounded need/s to be considered? solubility properties and dose of the API. only during a drug shortage. A The hygroscopicity of the API is the first B Capsule fill volumes in the order of D None of the above statements factor to consider. 30-40% are commonly used. are TRUE.

respectively. The results suggest that the compounded medication. The slow-release niacinamide capsules can be properties of particular inert cellulose compounded using hypromellose as the will determine the rate of release of Patricia Ullmann is a registered pharmacist with experience in sole release modifier and that the release the active agent. Therefor the choice of community and compounding pharmacy since the 1990s. She has been with Medisca Australia since 2012, heading the Technical mechanism is comparable to hydrophilic excipients requires careful consideration Support Services division and development, accreditation 21 polymer matrix-based systems. for improved patient outcomes and and facilitation of CPD training activities. Patricia has been a While numerous studies have shown in order to manage potential harm to contributing member of the TGA’s Pharmacy Manufacturing that hypromellose attenuates the release the patient. • Technical Working Group. of APIs from capsules, compounders need to be cognisant to avoid making claims 1. Jouyban A. Handbook of solubility data for pharmaceuticals. mixtures/pages/solubilities.html. about the time frame over which an API CRC Press, 2009; 2. 11. www.medisca.com.au/Pages/ProductDetails. will be released from a compounded 2. Loyd V Allen Jr, Clinical pharmaceutics and compounding, aspx?StockCode=2595&C=B&C2=112. Part V. Compounding Today. 2014 Oct 10; 11(40). 12. www.pccarx.com.au/products/pcca-exclusives/bases. slow-release capsule1,3 unless they have 3. Ferreira AO, Guia practico da farmacia magistral, Vol 1, ed 3. 13. Zur E. Compounding slow-release capsules: a comprehensive conducted appropriate dissolution Sao Paulo, Brazil: Pharmabooks, 2008;106-16. review and an excel spreadsheet for faster calailtaions of 4. Amidon GL, et al. A theoretical basis for a biopharmaceutic drug excipients. Int J Pharm Compd. 2013 Jan/Feb; 17(1):10-22. studies for their specific formulation. As classification: the correlation of in vitro drug product dissolution 14. Vu N, et al. Compounding slow-release pharmaceuticals. Int illustrated above, the release rate for a and in vivo bioavailability. Pharm Res. 1995 Mar;12(3):413-20. J Pharm Compd. 2009 Mar/Apr;13(2):144-5. 5. Bock U, et al. Validation of the Caco-2 cell monolayer system 15. Allen L. Prescription. Int J Pharm Compd. 2003 Nov/ specific slow-release formulation cannot for determining the permeability of drug substances according Dec;7(6):418. be specified with certainty unless studied, to the Biopharmaceutics Classification System (BCS). Across 16. Tiwari S, et al. Controlled release formulation of tramadol Barriers. 2003 Jul:1-7. hydrochloride using hydrophilic and hydrophobic matrix system. irrespective of whether the formulation 6. Pinheiro V, et al. In vitro evaluation of extemporaneously AAPS PharmSciTech. 2003;4(3):Article 31. was compounded or otherwise. As with all compounded immediate-release capsules. Int J Pharm Compd. 17. Li C, et al. The use of hypromellose in oral drug delivery. quality management systems monitoring 2013 Sept/Oct; 17(5):424-31. J Pharm Pharmacol. 2005;57:533-46. 7. Waiver of in vivo bioavailability and bioequivalence studies 18. Rowe RC, et al. Hypromellose. In: Handbook of pharmaceutical is required, in this case the response of for immediate-release solid oral dosage forms based on a excipients. 7th edn. London: Pharmaceutical Press, 2012:373-76. the patient needs to be monitored. biopharmaceutics classification system. Guidance for Industry. 19. https://pubchem.ncbi.nlm.nih.gov/compound/57503849. FDA, May 2015. 20. Pinheiro V, et al. Development and in vitro evaluation of In summary, the choice of 8. www.fda.gov/AboutFDA/CentersOffices/ extended-release theophylline matrix capsules. Braz J Pharm excipients in a compounded capsule OfficeofMedicalProductsandTobacco/CDER/ucm128219.htm. Sci. 2007 Apr/Jun;43(2). 9. Waiver of Bioequivalence Study. FDA, Aug 2000. 21. Radojkovic B, et al. Compounding of slow-release will directly affect bioavailability 10. Woods DJ. Formulation in pharmacy practice. 2nd edn. niacinamide capsules: feasibility and characterization. Int J and the pharmacokinetic profile of Available at www.pharminfotech.co.nz/manual/Formulation/ Pharm Compd. 2012;16(5):434-7.

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