Milind K. Biyani, PhD, is R&D consultant at Aspire Advisors Pvt. Ltd.

Milind K. Biyani

	Liquid-filled hard capsules (LFHCs) are typically composed of a shell of gelatin or hydroxypropyl methylcellulose (HPMC) and filled with compatible liquids or compositions that can flow below 70 

C. LFHC technology offers several advantages over other solid dosage forms (1). It is crucial, however, to select excipients that are compatible with capsule shell integrity and suitable for the purpose of a formulation.

. Hard-gelatin capsules contain 13–16% moisture. Hygroscopic vehicles such as glycerin, propylene glycol, and liquid polyethylene glycols (PEGs), however, cannot be used on their own because they will cause gelatin capsule shell brittleness and fracture. If the moisture content of a filled capsule does not change more than 2% at 65% relative humidity (RH) and 25 

C for six months, then the gelatin capsule will retain its integrity. PEG 400 and 600 can also distort HPMC capsules slightly due to swelling of shell walls caused by PEG diffusion. PEG 900 does not cause this problem. HPMC capsules (moisture content 3–8%) may be useful for moisture-sensitive and hygroscopic products and whenever capsules of vegetable source need to be used (2).

The dose of the drug substance and the quantity of an excipient that can be filled is limited by the capsule size. Commonly available hard capsule sizes for liquid filling along with their filling capacity are listed in 

. Normally, only 90% of the available volume is used for ensuring proper filling of liquids and sealing of the capsules.

	Table I. Hard-capsule sizes and their liquid-filling capacity.

The viscosity of the filled material should be in the range of 0.1–25 Pa•s (100–25000 cps), and filling can be achieved with accuracy and precision so that coefficient of variation (CV) of fill-weight values less than 1% are often achieved. Single components such as dietary supplements (e.g., evening primrose oil), or a two-component formulation where the bioactive substance dissolves in the excipient should fill satisfactorily at ambient temperature. Capsules need sealing if the liquid is flowable at ambient temperatures. Capsule sealing machines have been improved over the years to avoid leakages (2). 

Another consideration is the potential for crosslinking. A low concentration of aldehydes may be present in or produced during storage by some of the excipients used in liquid-fill formulations and may cause cross linking of gelatin, which consequently affects dissolution. To check this interaction, filled capsules are stored at 40 

C and 75% RH for six months. The capsules are emptied, cleaned, and then filled with acetaminophen as the dissolution reference material. Comparison of dissolution data for acetaminophen from the stored and reference capsules can provide evidence for interactions between the investigated fill material and the gelatin capsule. If this interaction is the problem, it can be overcome by the use of HPMC capsules that do not undergo these cross-linking reactions (3). 

	Excipients that have been found to be incompatible with hard-gelatin capsules include ethanol, glycerol, glycofurol 75, medium-chain monoglycerides (e.g., Alkoline MCM, Capmul MCM, Inwitor 308), PEG with a molecular weight (MW) less than 4000, Pharmasolve (N-methyl-2-pyrolidone), propylene glycol, Span 80, and Transcutol P (diethylene glycol monoethyl ether) (4). It may be possible, however, to incorporate small amounts of these excipients into liquid-fill formulations. The maximum tolerable concentration of an excipient should be determined experimentally. Formulations for hard-gelatin capsules that use mixtures containing PEG 200 have been published (5). 

	The numerous excipients that are compatible with hard-gelatin capsules are classified in three main categories by Cole (4) as follows:

	1.     Lipophilic liquids (e.g., refined oils, triglycerides, and esters)

	2.     Semi-solid lipophilics and viscosity modifiers (e.g., hydrogenated oils, cetostearyl/cetyl/stearyl alcohols, glyceryl esters, and Aerosil [fumed silica] for thixotropic gels)

	3.     Solubilizers, surfactants, emulsifiers, absorption enhancers (e.g., PEGs with MW more than 900 for HPMC capsules and more than 4000 for gelatin capsules, Tween 80, poloxamers).

	The scope of liquid filling has been increased by the use of thixotropic gels, thermosoftened systems, and self-emulsifying systems. In these semi-solid matrices (SSMs), the active substance is present as a particulate disperse phase.

A thixotropic gel undergoes shear thinning during filling followed by gel restructuring with an increase in its apparent viscosity in the filled capsule, which reduces tendency to leak from the capsule. For example, Miglyol 95% w/w and silicon dioxide (Aerosil 200) 5% w/w mixture and a liquid paraffin 95% w/wo hydrogenated castor oil (Thixcin R) 3% w/w and Aerosil 200 2% mixture were both filled satisfactorily with a CV of fill weight of 2.8% and 2% respectively (6). The particulate active substance is dispersed uniformly in the gel. Poloxamer/silicon dioxide gels have been also studied (7).

	In another example, a highly water-soluble drug, propantheline bromide, was dispersed in Miglyol 829/Aerosil 200 thixotropic gels. The drug release rate was dependent upon the silicon dioxide concentration. An increase in Aerosil percentage increased apparent viscosity of the triglyceride gel, causing a reduction in drug diffusion from the SSM (8).

Thermosoftened formulations are prepared at an elevated temperature to produce a formulation that is sufficiently mobile for satisfactory filling. A typical formulation may be based on a solid excipient (e.g., PEG or poloxamer that will melt below 70 

C) in which the active substance will melt, dissolve, or disperse. When cooled to ambient temperature, it will be a solid or semi-solid dispersion in the capsule. The filling process temperature is usually limited up to a maximum of 70

Cto avoid thermal damage to the capsule shell and to reduce operational hazards (2). As an example, Merck’s Entereg capsule, which was approved in the US in 2008, contains alvimopan suspended in PEG 3350.

	As another example, a study showed that ibuprofen, which has melting point 75 

C with PEG 6000, 10000, poloxamer, and Dynafill (a palmitic acid derivative of polyoxyethylenepolyoxypropylene block copolymer) (9).

	PEGs and poloxamers are stable for several hours at temperatures between 60 and 70

C that are commonly used for liquid-filling thermosoftened SSMs. PEGs of MW 4000–10000 and poloxamers have ideal physical properties for liquid-filling into hard capsules by the thermosoftening process, provided that aging does not adversely affect drug-release properties (2).

	Drug release from the SSM formulation could be altered by changing the hydrophilic-lipophilic balance of PEG stearate, the type and concentration of polymer, and the drug loading. This work led to a patent for Opticaps (10). 

This type of formulation is designed to self-emulsify in contact with aqueous media to form a fine dispersion. In each case, the basis of the formulation is a mixture of oil, a surfactant, and a co-surfactant, which can lead to improved drug delivery and bioavailability. A self-emulsifying drug delivery system (SEDDS) was formulated for Coenzyme Q

using Myvacet 9-45 (diacetylated monoglyceride) (40% w/w) as oil, Lebrasol (50%) w/w) as surfactant, and lauroglycol 10% w/w as co-surfactant. It showed a two-fold increase in bioavailability compared to a powder formulation, when tested in dogs. A self-nanoemulsified system (SNEDDS) based on a mixture of an essential oil, polyoxol 35 castor oil (Cremophor EL), and a medium-chain mono- and diglyceride mixture (Capmul MCM-C8) overcame some of the problems, such as low solubility and irreversible precipitation of active drug, associated with the SEDDS formulations (11).

	Applications of LFHC for particular drug formulations

Vancomycin HCl is a highly hygroscopic drug, and it was first available only as a dry powder in sealed ampoules. The problem of hygroscopicity was solved using an SSM formulation (12). The SSM formulation was prepared by a thermosoftening technique with PEG 6000 that protected the drug from moisture uptake and produced a stable and effective preparation in a liquid-filled hard-gelatin capsule. A similar approach was used to solve a problem with the hygroscopic and very unpalatable drug mercaptamine hydrochloride (13). An SSM formulation with PEG 6000 protected the drug from moisture uptake and masked the taste and smell of mercaptamine hydrochloride, which resulted in excellent compliance and the successful treatment of cystinosis in the children (2).

Sustained-release formulations have been prepared by using excipients that influence the hydrophilic-lipophilic balance of the SSM (2). Phenylpropanolamine was formulated as an SSM of arachis oil, beeswax, and silicon dioxide (14), and captopril is an SSM consisting of soybean oil and glycerol monostearate (15).

	Propranolol capsules contained a rapid-release phase of propranolol in oleic acid and a sustained-release phase of an erodible matrix of the same drug. The mixing of two phases was prevented by either inserting a hydrophilic Gelucire barrier between the two phases or by adding a hydrophobic Gelucire to the rapid-release phase to solidify it at temperatures less than 37

C (16). For example, isosorbide dinitrate retard capsules (Tillotts Pharma) contain 40% lactose and 60% Gelucire 50/02 as excipients. 

Micronization of the drugs in oil and filling the suspension in oil will minimize exposure to the potent drug. Agglomeration results in reduced solubility and hence reduced bioavailability, but filling the oily suspension instead of powder reduce the chances of agglomeration. Triamterene dosed at 20 mcg in a PEG mixture as a semi-solid filled in capsules shows a standard variation at 1.8%, compared to 3.1% for powder-fill capsules. The main reason for the improved standard deviation lies in volumetric filling, which does not show differences in density and homogeneity for semi-solids as it does for powders (17). The highest 

dissolution was when it was formulated with PEG 1000 and Gelucire 44/14; it was lower with PEG 1500 and lowest with PEG 6000 and PEG 4000 (18).

Biphenyl dimethyl dicarboxylate dissolved in a concentrate prepared from Tween 80, Neobee M-5, and triacetin provided improved bioavailability (19). Isotretinoin in sorbitan monooleate, soyabean oil, and stearoylpolyoxyl glycerides is approved as 505(b)(2) product against a softgel product (20). Another marketed product contains hydrogenated soyabean oil, polysorbate 80, soyabean oil, and white wax. 

Avoiding hepatic metabolic pathway for higher bioavailability. 

The undecanoate ester of testosterone exhibits much lower aqueous solubility than the native form, yet demonstrates higher oral bioavailability due to a greater lipophilicity and a greater propensity to enter the systemic circulation via the lymph, particularly when formulated as a lipid solution (Andriol Testocaps). It is dissolved in castor oil and propylene glycol monolaurate and filled as a soft-gelatin capsule (21) or LFHC.

	Formulating drug compounds in liquid or semi-solid excipients is used to target lymphatic transport (22) or to circumvent the impact of transporters (23) and metabolizing enzymes (24) in the gastrointestinal tract.

Liquid and semisolid filled capsules by their nature are resistant to crushing and powdering, and a drug is difficult to extract from waxes. For example, Oradur (Durect) uses a high-viscosity base matrix of sucrose acetate isobutrate.

	Large varieties of excipients are available for use in LFHCs based on the purpose of the formulation. Compatibility with the capsule shell and viscosity at the temperature of filling up to 70

C are most important considerations. With the advancements in machinery for sealing of hard capsules, more products could be developed as LFHCs.

41 (10) 36-41 (2017).
	2. G. Rowley, “Filling of Liquids and Semi-solids into Two Piece Hard Capsules,” in 

, F. Podczeck, B. Jones, Eds. (Pharmaceutical Press, 2

Ed., 2004), pp. 169-194.
	3. S. Nagata et al., 

. 131 (15) 88-91 (1986).
	6.  S. E. Walker et al., 

32, 389-393 (1980).
	7.  T. Saeed, G. Rowley, and P. A.Walters, 

Proceedings Pharmaceutical Technology Conference (Athens) 

16 (2) 217-224 (1997).
	8. P. A. Walters et al., 

18, 1613-1631 (1992).
	9. A. R. Hawley et al., 

18 (16) 1719-1739 (1992).
	10. Mepha Ltd, Aesch/BL, “Medicament with a delayed release of active ingredient,” US patent 4795643, Jan. 1989.
	11. S. Nazzal et al., 

235, 247-265 (2002).
	12. W. J. Bowtle, H. J. Barker, and J. Wodhams, 

12 (6) 86-91 (1988).
	13. F. K. Dixon et al., 

Proceedings Pharmaceutical Technology Conference (Strasbourg) 

41, 263-269 (1988).
	16.  S. J.Burns, 

. 134, 223-230 (1996)
	17. W. T. Ebert, 

1, 44-50 (1977).  
	18. Dordunoo, et al., 

Drug Development and Industrial Pharmacy 

17 (12) 1685-1713 (1991).
	19.  K. Chong-Kook, C.Yeon-Ju, and J. Zhong-Gao, 

70, 149-155 (2001).
	20.  G.F. Webster, J.J. Leyden, and J.A. Gross. 

69, 762-767 (2013).
	21.  E. Nieschlag et al., 

79, 366-374 (1975).
	22.  Griffin and O’Driscoll, 

. 58, 917-925 (2006).23.  Martin-Facklam, et al., 

. 53, 576-581 (2002).
	24.  Gao and Morozowich, 

	When referring to this article, please cite it as M. K. Biyani, " Selecting Excipients for Liquid-Filled Hard Capsules," 

Pharmaceutical Technology Europe APIs, Excipients, & Manufacturing

	Milind K. Biyani, Ph.D.(Tech.) is R&D consultant at Aspire Advisors Pvt. Ltd., Mumbai, India, 

Articles

Thixotropic gels, thermosoftened systems, and self-emulsifying systems have expanded the range of potential excipients for liquid-filled hard capsules (LFHC).

Selecting Excipients for Liquid-Filled Hard Capsules

Oral-solid dosage (OSD) drugs can be formulated in tablet or capsule form. Some drugs are available only as capsules or tablets, and some are available as both. Various types of capsules, with shells made of different materials, are available. When choosing a capsule type, formulators should consider factors such as the shell’s barrier to water and oxygen, reactivity, and the material it is made of.

	The most widely used capsules can be classified as shown in 

 and discussed in the following sections. Dry-filled capsules include mainly hard gelatin and hard hydroxypropyl methylcellulose or hypromellose (HPMC) capsules. Liquid-filled capsules include hard capsules (gelatin or HPMC) and softgel gelatin capsules.

	The larges size (000) is mainly used in veterinary practice. Fill weights increase with the size of the capsule as well as with the bulk density of the filled material, which can range from 0.3–1.5 g/cc. Fill weights in the smallest capsules might be 39 mg, for example; the largest may weigh 1425 mg.

	The shell of hard gelatin capsules contain 13–16% water. Storage of hard-gelatin capsules at very low humidity can cause them to turn brittle. Gelatin capsules do not protect hygroscopic materials from atmospheric water vapor because moisture can diffuse through the gelatin wall. If stored at high humidity, the capsules become flaccid. In such cases, primary packaging material such as aluminum strip packing, moisture barrier blister foil (e.g., Aclar), or bottle packs should be used. 

The gelatin used in the manufacture of most common capsules is obtained from collagenous material by hydrolysis. Gelatin is a natural, safe, non-allergenic, clean, and economical ingredient. The two-piece hard gelatin capsule is available in a range of sizes; from largest to smallest, these sizes are 000, 00el, 00, 0xel, 0el+, 0el, 0, 1el, 1, 2, 3, 4, 5. 

 HPMC capsules are stable at low humidity levels, have low moisture content (3–8%), and low static charge. These natural capsules are available from size 00 to 4. HPMC capsules are suitable for highly reactive molecules (because they have no cross-linking reactions). Compared to hard gelatin, HPMC is more suitable for moisture-sensitive products, hygroscopic products, and for low relative-humidity applications. HPMC is not of animal origin and does not pose a risk of contamination with organisms that cause bovine spongiform encephalopathy (BSE) or transmissible spongiform encephalopathy (TSE). HPMC capsules are used in a wide range of OSD pharmaceuticals as well as nutraceuticals, dietary supplements, and herbal products, due to the vegetarian nature of HPMC. 

 Marinecaps are made from fish gelatin and do not pose risk of BSE or TSE. They are preferred for filling marine supplements such as EPA [eicosapentaenoic acid]-rich fish oil.

 Starch capsules are made from potato starch. Their dissolution is pH independent, and they are suitable for enteric coating. The moisture content of starch capsules ranges between 12–14% w/w, with more than 30% being tightly bound (1). 

 These vegetarian capsules are made from tapioca, which is naturally fermented into pullulan. They provide a high barrier to oxygen.

. Capsules made from PVA can be used for filling insoluble drugs dissolved in polyethylene glycol (PEG) 400. PEG 400 when used as single vehicle is not compatible with other hard capsules. The oxygen permeability of PVA is low, resulting in a high barrier to oxygen.

 Two-piece hard capsules made of either gelatin or HPMC can be used for filling and band sealing non-aqueous liquid, paste, suspension, hot melts, and other vehicles that melt up to 70 °C and flow easily. LFHC can also be filled with tablets, pellets, or other capsules as combination fill. LFHC can be used for moisture-sensitive drugs. These can be a cost-effective alternative to some soft gelatin capsule products and can also enhance bioavailability and improve product stability. Liquid encapsulation technology helps overcome many problems associated with the use of softgel capsules including high cost, waste, cross-contamination, migration of the drug into the capsule shell, and issues with low bioavailability. Liquid-filled and semi-solid capsules by their nature are resistant to crushing and powdering and therefore provide a good basis for developing an abuse-resistant formulation. These capsules can also be enteric coated. HPMC hard capsules do not become brittle when they lose water (2).

 SGC have soft, globular, gelatin shells somewhat thicker than that of hard gelatin capsules. The gelation is plasticized by the addition of glycerin, sorbitol, or a similar polyol. It may contain preservative to prevent the fungal growth. Large-scale production methods are generally required for the preparation of SGC.

 The growing interest in capsules as a formulation is consumer driven. Consumers prefer capsules because they are tasteless, odorless, and easier to swallow. Capsules are also considered to work faster and better. In a study conducted by Burke Marketing Research, 1000 patients were asked about the form of drug administration they preferred, and more than half (54%) chose capsules (3). Another study, conducted with several hundred patients in two hospitals in Copenhagen and published in 2001, found that 66% preferred capsules (3). This preference has prompted pharmaceutical manufacturers to market products in capsule form even if the product already has been produced in tablet form. 

 Most filled capsules disintegrate in 5–10 minutes. Some of the immediate release tablets may have much lower disintegration time. Once a capsule disintegrates, however, dissolution may be faster and dissolution levels achieved may be similar to tablets at 15 minutes. HPMC capsule shells can lead to rapid dissolution. However, these differences will not necessarily produce considerable alterations in the pharmacokinetic profiles of the drug product because the f2 value used to determine dissolution differences is often too discriminating, particularly when the dissolution is very fast relative to permeation and/or absorption is very fast relative to disposition (4). 

Capsules are easier and faster to develop and manufacture in comparison to other OSD forms because the capsule manufacturing process involves fewer steps and a lower number and quantity of excipients. For example, as per studies conducted by Aspire Advisors, Acetazolamide 250 mg tablet weight is 516 mg but Acetazolamide ER 250 mg capsule fill weight is only 328 mg. Some coarse, free-flowing, Biopharmaceutical Classification System Class I drugs can be filled directly into capsules. Capsules can also be used for poorly compressible drugs.

	Capsules provide relatively better stability than other OSD forms. Encapsulation does not create high heat and pressure, thus heat-sensitive drugs can be more readily formulated as capsules. Capsule walls can be made opaque, providing protection for light-sensitive compounds. Sealed hard gelatin caps can be good oxygen barriers. As capsules generally require fewer excipients, drugs that are sensitive to or highly reactive with other chemicals may be more readily formulated as capsules.

	Further, due to fewer processing steps, capsules can minimize human exposure to potent drugs. Capsules reduce airborne dust levels, lowering the risk of cross-contamination and offer improved content uniformity particularly at low dosage levels and for potent drugs. Overall, they reduce the capital requirements for dedicated facilities, air-handling, and process equipment. 

 Encapsulation technology has made progress in recent years. For example, soft gelatin capsules and LFHC are increasingly being used for filling and/or sealing (band sealing in case of LFHC) of liquid and pastes. Furthermore, a single capsule can now encapsulate not only powders or granules, but also one or more ingredients that are in liquid, pellet, tablet, or another capsule form. Incompatible ingredients can thus be combined into a single capsule, which helps to develop combination products. 

	Enteric coating of hard capsules or use of enteric hard capsules further expands the scope of capsules usage (5). In addition, capsules can be used for active ingredients that need modified release. Modified-release capsules can now be developed that disperse freely in the gastrointestinal tract, providing more uniform distribution of drug into the bloodstream. These capsules help to maximize absorption and minimize side effects. They also reduce inter- and intra-patient variability. Calcifediol and oxycodone extended release (ER) capsules are two examples of ER capsules approved in 2016 as new drug applications. 

	Dissolving the active ingredient in a mixture of liquids, semi-solids, or hot-melts can result in better solubility and higher absorption. For example, isotretinoin solubilized in sorbitanmonooleate, soybean oil, and stearoylpolyoxylglycerides filled in hard capsules (marketed as Absorica in the United States) gave higher absorption in fasted state than the original softgel product Roccutane/Accutane (6). Those drugs that cannot be solubilized in this manner may be formulated as a self-emulsifying drug delivery system.

	Capsules are also useful for clinical trials. Specialized capsules for clinical trials are unique two-piece gelatin capsules that are specially designed to carry out double-blind studies during clinical trials. After closure (locking), the elongated cap closes tightly on the body. Once locked, only the dome of the body is visible, making it almost impossible to open the capsule. 

	Capsules can be developed faster than tablets for new chemical entities. Because Phase I and II clinical trials are mostly carried out using capsules, additional bioequivalence/bioavailability studies are needed when converting from capsules to tablets. Moving a product to market one year faster can give one year more effective patent life. Similarly, other types of innovations and FDA applications, such as abbreviated new drug applications, can be marketed faster.

 Capsule manufacturing companies have developed a unique technology that enables capsules to be printed in multiple colors, which creates brand differentiation and serves as an effective anticounterfeit measure. Further, it is now possible to imprint brand logo, brand name, and graphics on the capsule, providing further brand identity (7).

	In summary, capsules are an attractive OSD form that enjoys patient preference, improved pharmacokinetic profile, faster development, and formulation flexibility. In addition, capsule formulations offer brand recognition in a crowded pharmaceutical market. Switching to capsules from other OSD forms also gives manufacturers an excellent opportunity to get out of the competitive environment of generics while still enjoying a development process that eliminates most preclinical studies as well as extensive safety and efficacy tests. 

Theory and Practice of Industrial Pharmacy

 by Lachmann and Lieberman, R.K. Khar, S. P. Vyas, F.J. Ahmad, and G.K. Jain, Eds. (CBS Publishers & Distributors, 4th ed., 2013), pp. 546-578.
	2. G. Rowley, “Filling of Liquids and Semi-solids into Two Piece Hard Capsules” in 

, F. Podczeck, B.E. Jones, Eds. (Pharmaceutical Press, 2nd ed. 2004), pp. 169-194.
	3. A.B.A. Overgaard, et al.,  

 23 (5) 185-188 (2001).
	4. J. Al-Gousous, et al., AAPS Annual Meeting and Exposition Poster Number M3293 (2016).
	5. H. Schaub, C. Scialdone, and J.V. Carey, 

 34, 4-8 (2012).
	6. G.F. Webster, et al., 

 69, 762-767 (2013).
	7. ACG World, “Drug Anticounterfeiting Solutions,” www.acg-world.com/resources/drug-anti-counterfeiting-solutions.php, accessed Aug. 25, 2017.

	When referring to this article, please cite it as M. Biyani, "Choosing Capsules: A Primer," 

	Milind K. Biyani, PhD, is R&D consultant at Aspire Advisors Pvt. Ltd., A-101, Mahavir Darshan, Charkop-2, Mumbai-400067, India, drmilind@aspire-advisors.net. 

Capsules offer certain benefits over tablets for oral-solid dosage drugs, and several types of capsules are available.