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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. 78 AUGUST 2017 AJP CPD continuing professional development 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 AUGUST 2017 79 EDUCATION PRACTICE UPDATE 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

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