Liquid and Semi-solid Formulation Technologies


1. Lipid-based Drug Delivery Systems

Up to 70% of NCEs in current pipelines suffer from poor aqueous solubility (BCS Class II) as depicted in Figure 1. Lipid-based drug delivery systems have often been used successfully for the development and commercial manufacture of products containing BCS Class II and IV compounds as evidenced by the number of approved products marketed as soft gelatin capsules (see Table 1). More recently, developers have investigated lipid-based systems for macromolecule (BCS Class III) delivery.

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Table 1.Examples of Approved Class II and IV Compounds Formulated Using a Lipid-based Soft Gelatin Formulation

Agenerase
(amprenavir)		 Aloxi
(palonosetron HCl)		 Amitiza
(lubiprostone)		 Aptivus
(tipranavir)
Avodart
(dutasteride)		 Depakene
(valproic acid)		 Hectorol
(doxercalciferol)		 Lamprene
(clofazimine)
Marinol
(dronabinol)		 Neoral
(cyclosporine A)		 Nimotop
(nimodipine)		 Norvir
(ritonavir)
Rocaltrol
(calcitriol)		 Sandimmune
(cyclosporine A)		 Stavzor
(valproic acid)		 Tirosint
(levothyroxine Na)
VePesid
(etoposide)		 Zemplar
(paricalcitol)

Lipid-based delivery systems most often rely on presentation of the active substance in a solubilized form to enhance bioavailability. This strategy relies on the premise that drugs need to be in solution for adequate GIT absorption. Starting with the drug in solution circumvents the dissolution step associated solid-form technologies such as nanoparticulate and amorphous solids. Poorly water-soluble drugs are more likely to dissolve in lipid excipients than aqueous-based solvents (“like dissolves like”).

Lipid-based drug delivery systems range from simple solutions of drugs in oil to more complex mixtures of drugs dissolved in lipids, surfactants, co-surfactants and co-solvents. The Lipid Formulation Classification System (Table 2) was initially introduced in 2000 as a way of classifying these various formulations based on their composition and the resulting hydrophilic/lipophilic balance of the excipient blend. This system was later further refined to include the in-vitro behavior of these lipid-based formulations based upon dispersion and digestibility, which potentially would also be a reasonable predictor of their in-vivo performance.

Composition (% w/w)
Component Type I Type II Type IIIA Type IIIB Type IV
Triglycerides or mixed glycerides 100 40-80 40-80 <20 -
Water Insoluble Surfactants (HLB < 12) - 20-60 - - 0-20
Water Soluble Surfactants (HLB > 12) - - 20-40 20-50 30-80
Hydrophilic cosolvents - - 0-40 20-50 0-50
In-vitro behavior
Physical state upon dispersion Coarse emulsion SEDDS SEDDS/SMEDDS SEDDS/SMEDD SMEDDS Micellar systems
Behavior upon dispersion Limited importance Solvent capacity unaffected Some loss of solvent capacity Potential loss of solvent capacity Potential loss of solvent capacity
Digestibility Digestible Digestible Possibly inhibited Possibly inhibited Non digestible

As reflected in the Lipid Formulation Classification System (Table 2), lipid-based formulations can form coarse emulsions, emulsions, micro-emulsions or micellar systems upon dispersion in the gastrointestinal fluids. Type I and II formulations typically disperse as coarse emulsions and emulsions in GI fluids while Type III and IV formulations disperse as micro-emulsions and micelles. The former (Type I and II) often depend on digestion as the mechanism by which they are to enhance bioavailability. The latter (Type III and IV) are often referred to as self emulsifying drug delivery systems (SEDDS) and self micro-emulsifying drug delivery systems (SMEDDS) and require the addition of higher proportions of surfactants (hydrophilic surfactants with HLB’s greater than 12) to self-emulsify upon contact with the gastric fluids producing very fine dispersions of active containing lipid droplets. These thermodynamically stable systems are often less subject to variability (intra/inter patient variability and food effect). As formulators move toward Type IIIB and IV systems that rely on higher quantities of hydrophilic surfactants to promote fine dispersions, these surfactants may also inhibit the formulation’s digestibility.

Given the importance of dispersion and digestion in the design of a lipid-based formulation, formulation scientists often employ phase diagrams and pH-stat methods for the in-vitro assessment of lipid-based delivery systems and to predict their in vivo behaviour to ensure that the drug substance remains in solution upon dipersion and digestion.

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Hydrophilic Formulations

Hydrophilic formulations are composed of mixtures of solvents, co-solvents and high HLB surfactants designed to achieve maximum drug solubility . Technically, Type IV formulations under the Lipid Formulation Classification System are considered hydrophilic. Upon ingestion, these formulations readily mix with the aqueous contents of the stomach. As a result, poorly soluble drugs either stay in solution or, in the some cases, the drug may precipitate in the gastric fluids as a fine suspension (for example a drug that is a weak acid) with a high surface area, which promotes rapid dissolution and a corresponding improvement in bioavailability. The inclusion of surfactants in the formulation aids in forming micellar solutions or re-dissolution of precipitated drug . One particularly useful approach often employed to maximize the solubility of a weakly acidic or weakly basic drug in a hydrophilic solvent such as PEG 400 is to partially neutralize these drugs appropriately with acid or base. The quantity of acid or base added determines how much of the corresponding salt of the weak acid or weak base exists. The combination of both species (the corresponding salt of the weak acid or weak base plus the remaining free weak acid or weak base) often results in a greater solubility in PEG than for either species individually.

Dosage Forms for Liquid and Semi-solid Formulations

Once a lipid-based or hydrophilic formulation has been selected based on dispersibility and digestibility properties, a suitable final dosage form must be selected for a commercially viable product. Lipid-based and hydrophilic formulations can exist as a continuum of physical states or forms ranging from liquids to semi-solids to solids. Two important physical properties that influence final dosage form selection are the melting range and the hydrophilic/lipophilic balance (HLB) of the formulation. Chemical stability of the lipid-based formulation (e.g., oxidation and thermal stability), and the ability of the final dosage form to protect such formulations from degradation over the product’s shelf-life are additional considerations.

Liquid and semi-solid formulations can be filled directly into soft elastic capsules or hard shell capsules provided the formulations are suitable for this operation at room or elevated temperatures. Soft elastic capsules can be manufactured using the rotary-die process with gelatin shells (softgel capsules) or gelatin-free shells (Vegicaps® capsules). Similarly, liquid and semi-solid formulations can be filled into hard capsules (liquid-filled hard shell capsules) with either gelatin shells or gelatin-free (HPMC) capsules.

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  • 1. Softgel Capsules

    Used for both lipophilic and hydrophilic oral formulations, softgel capsules (also known as “soft elastic capsules”) consist of a hermetically sealed gelatin or gelatin-free shell surrounding the drug product. While gelatin derived from animal sources is most widely used for pharmaceutical products, plant-derived (vegetarian) softgel capsules are available and often used for dietary supplements.

    Softgel capsules are manufactured using using either the rotary-die or the drop-formulation process. The form-fill-seal rotary-die process, invented by R.P. Scherer, is most widely used today .

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    Softgels provide numerous benefits as a commercializable dosage form for oral delivery of lipid-based and hydrophilic formulations, and are considered the dosage form of choice for enhancing the bioavailability of a wide range of poorly-soluble drug substances. Further, softgels and their associated manufacturing process minimize the exposure of oxygen-sensitive materials, such as lipid excipients, to the atmosphere, thereby providing acceptable stability and product shelf-life. An added benefit, from the patient’s perspective, is that softgels are easier to swallow, compared to tablets, for larger sized dosage units. From a manufacturing perspective, the processing of fill liquids and their encapsulation into softgels is well-understood and proven at commercial-scale. Since lipid-based or hydrophilic fill formulations can be filled directly into softgels with no further downstream processing steps, scale-up issues are minimized and development cycle times shortened.

  • 2. Vegicaps® Capsules

    Vegicaps® capsules are nearly identical to softgels, but the animal-derived gelatin is replaced with plant polysaccharides (carrageenan and modified starch). Vegicaps® capsules significantly expand the range of fill formulations suitable for softgels. Specifically, heated fills up to 65°C - 75°C can be encapsulated using the Vegicaps® technology as well as fills that are alkaline or cause cross-linking of gelatin-derived shells. Along with softgels, Vegicaps® capsules enable the encapsulation of a broad range of fill formulations including liquid and semi-solid fills, and lipophilic to hydrophilic fills.

    In addition to the above technical benefits, patients and consumers who prefer non-animal-derived products for health or personal reasons now have an option in a softgel format. Like softgels, Vegicaps® are readily manufactured using the rotary-die process and have a proven track record of use in the dietary supplement products.

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  • 3. Liquid-filled Hard Shell Capsules

    Liquid-filled hard shell capsules consist of a pair of hard gelatin capsule “halves” that are joined together after filling with a dose of liquid of semi-solid fill formulation.5 The bodyand cap of liquid-filled hard shells are sealed, using either a process that applies a gelatin band to the body-cap joint, or with a hydroalcoholic spray that is drawn up between the cap and body to fuse the halves of the capsule. As with softgels, liquid-filled hard shell capsules are available in gelatin-based shells or gelatin-free (typically HPMC) capsules. As a rule, liquid-filled hard shells are best suited for the encapsulation of semi-solid formulations. However, compatibility issues are generally experienced with hydrophilic and amphiphilic formulations (liquid or semi-solid) with elevated HLBs.

1Hom, F.S., and Jimerson, R.F. Capsules, Soft. In Swarbrick, J., and Boylan, J.C., eds., Encyclopedia of Pharmaceutical Technology, Volume 2., Marcel Dekker, Inc., New York, 1990; 269-284

2Jimerson, R. F., Softgel (Soft Gelatin Capsule) Update Drug Dev Ind Pharm (Interphex ’86 Conference). 1986; 12 (8 & 9): 1133-1144<

3Stanley, J.P. Soft Gelatin Capsules. In Lachman, L., Lieberman, H.A., and Kanig, J.L., eds., The Theory and Practice of Industrial Pharmacy,Lea & Febiger, Philadelphia, 1970; Chapter 13. 359-384

4Bergstrom, D.H., Tindal, S., and Dang, W. Capsules, Soft. In Swarbrick, J., ed, Encyclopedia of Pharmaceutical Technology, 3rd Edition.Informa Healthcare USA, 2006; 419-430

5Cadé, D. Cole, E. T., Mayer, J. Ph. and Wittwer, F. (1986) Liquid Filled and Sealed Hard Gelatin Capsules Drug Development and Industrial Pharmacy, 12(11-13): 2289-2300

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