Solubilizing Excipients in Oral and Injectable Formulations

Review Article Solubilizing Excipients in Oral and Injectable Formulations Robert G. Strickley1,2 Received June 10, 2003; accepted November 5, 2003 A review of commercially available oral and injectable solution formulations reveals that the solubilizing excipients include water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfox- ide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-�-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids/semi-solids (beeswax, d-�-tocopherol, oleic acid, medium-chain mono- and diglyc- erides), various cyclodextrins (�-cyclodextrin, �-cyclodextrin, hydroxypropyl-�-cyclodextrin, and sulfo- butylether-�-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphos- phatidylglycerol, L-�-dimyristoylphosphatidylcholine, L-�-dimyristoylphosphatidylglycerol). The chemi- cal techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions. KEY WORDS: excipients; oral formulations; parenteral formulations; solubilization. INTRODUCTION The excipients used to solubilize drugs in oral and inject- able dosage forms include pH modifiers, water-soluble or- ganic solvents, surfactants, water-insoluble organic solvents, medium-chain triglycerides, long-chain triglycerides, cyclo- dextrins, and phospholipids. This review focuses on the solu- bilizing excipients in commercially available pharmaceutical solution formulations. The published information on oral for- mulations includes only the list of excipients (1–3), whereas the published information on injectable formulations includes the exact amounts of the excipients (2–10). Two key aspects of any successful solution formulation are solubility and sta- bility. The solvent system chosen must also be able to solu- bilize the drug at the desired concentration and must provide an environment where the drug has sufficient chemical sta- bility. Sufficient stability is normally defined as <5–10% deg- radation over 2 years under the specified storage conditions, but the topic of stability (11) is beyond the scope of this review. THEORY Solubility at constant temperature and pressure involves the free energy of the solid (GsolidT, P) and the free energy of the molecules in solution (GsolutionT, P). The free energy of a specific solid is fixed (i.e., a property of that solid), but the free energy of the molecules in solution is a function of the solvent and the solution concentration (N). When the solu- tion free energy is less than the solid free energy, molecules will dissolve from the solid until the free energy of the mol- ecules in solution equals the free energy of the solid. At satu- ration equilibrium solubility, the free energy of the solid equals the free energy of the molecules in solution, Eq. (1). GsolidT,P = GsolutionT,P �Nsaturation� [1] An increase in solubility at constant temperature and pressure can occur by increasing the free energy of the solid either by chemical means such as varying the salt form or by physical means such as creating an amorphous solid, poly- morphs, or particle size reduction (i.e., micronization or nano- particles). However, the increase in equilibrium solubility via solid-state alterations is only maintained if the solid phase at equilibrium remains the same as the initial solid. Thus, solu- bility manipulation via solid-state properties is inherently 1 Formulation & Process Development, Gilead Sciences Inc., Foster City, California 94404. 2 To whom correspondence should be addressed. (e-mail: rstrickley@ gilead.com) ABBREVIATIONS: BHA, butylated hydroxy anisole; BHT, butyl- ated hydroxytoluene; D5W, 5% dextrose in water; DMPC, L-�- dimyristoylphosphatidylcholine; DMPG, L-�-dimyristoylphosphati- dylglycerol; DSPG, distearoylphosphatidylglycerol; EDTA, ethylene- diaminetetraacetic acid; HP-�-CD, hydroxypropyl-�-cyclodextrin; HSPC, hydrogenated soy phosphatidylcholine; IM, intramuscular; IV, intravenous; LP, lyophilized powder; PEG, polyethylene glycol; PG, propylene glycol; SAIB, sucrose acetate isobutyrate; SBE-�-CD, sulfobutylether-�-cyclodextrin; SC, subcutaneous; SCS, sodium cho- lesteryl sulfate; SEEDS, self-emulsifying drug delivery system; TPGS, (d-� tocopheryl polyethylene glycol 1000 succinate); TRIS, tris(hy- droxymethyl)aminomethane; WFI, water for injection. Pharmaceutical Research, Vol. 21, No. 2, February 2004 (© 2004) 201 0724-8741/04/0200-0201/0 © 2004 Plenum Publishing Corporation more difficult to achieve and to reproducibly control than is alteration of the solution properties. A more common and controlled means to increase solu- bility is by decreasing the chemical potential of the molecule in solution, �solution, by the appropriate choice of solubilizing excipient(s). Chemical potential is the incremental increase in the free energy of a molecule in solution per incremental increase in the number of molecules in solution, Eq. (2). Ex- cipients that solubilize a molecule via bulk solution properties provide a solution environment in which the chemical poten- tial of the molecule in solution is reduced, thereby requiring a higher solution concentration (i.e., solubility) to reach a solution free energy that matches the solid free energy, Eq. (3). �solution = �dGsolution�dNsolution)T,P [2] dGsaturated solution = (�solution)(Solubility) [3] Excipients that solubilize a molecule via specific interac- tions such as complexation interact with the molecule in a noncovalent manner that lowers the chemical potential of the molecules in solution. These noncovalent bulk and specific solubility-enhancing interactions are the basis of the phenom- enon that “like dissolves like” and include van der Waals forces, hydrogen bonding, dipole–dipole and ion–dipole in- teractions, and in certain cases favorable electromagnetic in- teractions. If the molecule is ionizable, then pH adjustment can be used to increase water solubility because the ionized molecu- lar species has higher water solubility than its neutral species. Equations (4) and (5) show that the total solubility, ST, is a function of the intrinsic solubility, So, and the difference be- tween the molecule’s pKa and the solution pH. The intrinsic solubility is the solubility of the neutral molecular species. Weak acids can be solubilized at pHs above their acidic pKa, and weak bases can be solubilized at pHs below their basic pKa. For every pH unit away from the pKa, the weak acid/ base solubility increases 10-fold. Thus, solubility enhance- ments of >1000-fold above the intrinsic solubility can be achieved as long as the formulation pH is at least 3 U away from the pKa. Adjusting solution pH is the simplest and most common method to increase water solubility in injectable products (5–10), but is not a major focus of this review be- cause the excipients used to alter the solution pH are com- monly used buffers (5–8). For a weak acid ST = So (1 + 10pH-pKa) [4] For a weak base ST = So (1 + 10pKa-pH) [5] Cosolvents are mixtures of miscible solvents and are of- ten used to solubilize water-insoluble drugs. Molecules with no ionizable group(s) cannot be solubilized by pH adjust- ment, and thus a cosolvent approach is often used. Solubility typically increases logarithmically with a linear increase in the fraction of organic solvent(s) as illustrated in Eq. (6). If the cosolvent is composed of one organic solvent and water (i.e., a binary mixture), the solubility can be empirically described as in Eq. (6) by assuming that the total free energy of the system is equal to the sum of the free energy of the individual components (12), log Sm = flog Sc + (1 − f)log Sw [6] where Sm is the total solubility in the cosolvent mixture, Sc is the solubility in pure organic solvent, Sw is the solubility in water, and f is the fraction of organic solvent in the cosolvent mixture. Equation (6) can be simplified to Eq. (7): log Sm = log Sw + f� [7] where � = log acw − log acc [8] and acw and acc are the activity coefficients of the molecule in water and solvent, respectively. The parameter, �, which is slope of the plot of log Sm vs. f, can be used as a measure of the solubilization potential of a given cosolvent. If the cosolvent mixture contains more than two organic solvents (i.e., a ternary or higher cosolvent mixture such as a microemulsion) the total drug solubility can be approximated by a summation of solubilization potentials as in Eqs. (9) and (10): log (Sm�Sw) =∑ (fi�i) [9] log Sm = log Sw +∑ (fi�i) [10] Complexation between a ligand and a complexing agent can increase the ligand’s solubility if both the ligand and com- plexing agent have the proper size, lipophilicity, and charge that allow for favorable solubility-enhancing noncovalent in- teractions. If the ligand and complexing agent combine to form a 1:1 complex, the total ligand solubility, ST, can be described by Eq. (11), ST = So + K11SoLT��1 + K11So� [11] where So is the ligand solubility in water, K11 is the formation constant of the 1:1 complex, and LT is the total concentration of the complexing agent (ligand) (13). Thus, the total ligand solubility is a linear function of the concentration of the com- plexing agent. Using cyclodextrins as complexing agents, solu- bility enhancements as high as 104 to 105 can be achieved. Emulsions are a mixture of water, oil, surfactant, and other excipients. If a water-insoluble molecule is soluble in oil, then it can be solubilized in an emulsion where it parti- tions into the oil phase. The total solubility in an emulsion, STe, is the summation of concentrations in the aqueous and oil phases (14). The concentration in the aqueous phase is the solubility in that aqueous phase, SA, and the concentration in the oil phase can be approximated by the product of the molecule’s solubility in the pure oil, Soil, multiplied by the fraction of the oil in the emulsion, foil, as described in Eq. (12): STe, = SA + �Soil)(foil,� [12] ORAL FORMULATIONS The vast majority of commercially available oral formu- lations are solid dosage forms such as tablets or capsules, but there are many solubilized oral formulations such as oral so- lutions, syrups, elixirs, or solutions filled into soft or hard capsules. The reasons for pursuing a solubilized oral formu- lation include enhancing the oral bioavailability of a poorly water-soluble molecule, a measurable formulation for dose modification, a formulation for patients who cannot swallow tablets or capsules, or a solution for a sore throat/cold rem- edy. Table I is a list of selected, commercially available solu- bilized oral formulations arranged alphabetically by drug Strickley202 Table I. List of Selected Commercially Available Solubilized Formulations for Oral Administration Molecule/ Trade Name/ Company/ Indication Chemical structure Water solubility Commercial oral formulation Excipients Amprenavir/ Agenerase/ Glaxo SmithKline/ HIV 36 �g/ml (34) 1. Soft gelatin capsule 50, 150 mg 2. Oral solution 15 mg/ml Oral bioavailability from the solu- tion is 13% less than the capsules (21) 1. TPGS (280 mg in the 150 mg cap- sule) PEG 400 (247, 740 mg) Propylene glycol (19, 57 mg) 2. TPGS (∼12%) PEG 400 (∼17%) Propylene glycol (∼55%) Sodium chloride Sodium citrate Citric acid Flavors/sweeteners Bexarotene/ Targretin/ Ligand/ Antineoplastic Insoluble in water (2) Soft gelatin capsule 75 mg PEG 400 Polysorbate 20 Povidone BHA Calcitrol/ Rocaltrol/ Roche/ Calcium regulator Relatively insoluble in water (2) 1. Soft gelatin capsule 0.25, 0.5 �g 2. Oral solution 1 �g/ml 1. Fractionated tri- glyceride of co- conut oil (me- dium-chain tri- glyceride) 2. Fractionated tri- glyceride of palm seed oil (me- dium-chain tri- glyceride) Clofazimine/ Lamprene/ Geigy (1960)/ Antileprosy Virtually insoluble in water (3) Soft gelatin capsule 50 mg Beeswax Plant oils Propylene glycol Cyclosporin A/ I. Neoral/ Novartis/ Immunosuppressant, prophylaxis for organ transplant rejection Slightly soluble in water (23) 1. Soft gelatin capsule 25, 100 mg 2. Oral solution 100 mg/ml “im- mediately forms a microemulsion in an aqueous environment” (2) Oral bioavailability is 20–50% (2) 1. Ethanol 11.9% Corn oil-mono-di-- triglycerides Polyoxyl 40 hy- drogenated cas- tor oil (Cremo- phor RH 40) Glycerol Propylene glycol dl-�-tocopherol 2. Ethanol 11.9% Corn oil-mono-di- triglycerides Polyoxyl 40 hy- drogenated cas- tor oil (Cremo- phor RH 40) dl-�-tocopherol Propylene glycol Solubilizing Excipients in Oral and Injectable Formulations 203 Table I. Continued Molecule/ Trade Name/ Company/ Indication Chemical structure Water solubility Commercial oral formulation Excipients Cyclosporin A/ II. Sandimmune/ Novartis/ Immunosuppressant, prophylaxis for organ transplant rejection 1. Soft gelatin capsule 25, 50, 100 mg 2. Oral solution 100 mg/ml Oral bioavailability is <10–89% (2) 1. Ethanol 12.7% Corn oil Glycerol Polyoxyethylated glycerides (La- brafil M-2125CS) 2. Ethanol 12.5% Olive oil Polyoxyethylated oleic glycerides (Labrafil M-1944CS) Further dilute with milk, chocolate milk, or orange juice before use. Cyclosporin A/ III. Gengraf/ Abbott/ Immunosuppressant, prophylaxis for organ transplant rejection Hard gelatin capsule 25, 100 mg “forms an aqueous dis- persion in an aqueous environ- ment”, Orally bioequiva- lent to Neoral (2) Ethanol 12.8% Polyethylene glycol Polyoxyl 35 castor oil (Cremophor EL) Polysorbate 80 Propylene glycol Sorbitan monoole- ate Digoxin/Lanoxin/ Glaxo SmithKline/ Treatment of mild to moderate heart failure Practically insoluble in water (2) 1. Soft gelatin capsule 50, 100, 200 �g Oral bioavailability is 90–100% (21) 2. Elixir pediatric 50 �g/ml Oral bioavailability is 70–85% (21) 1. PEG 400 Ethanol 8% Propylene glycol 2. Ethanol 10% Methyl paraben 0.1% Citric acid Flavor Propylene glycol Sodium phosphate Sucrose Doxercalciferol/ Hectorol/ Bone Care/ Management of secondary hyperparathyroidism associated with chronic renal dialysis Relatively insoluble in water (2) Soft gelatin capsule 2.5 �g BHA Ethanol Fractionated tri- glyceride of co- conut oil (me- dium-chain tri- glyceride) Dronabinol/ Marinol/ Roxane and Unimed/ Anorexia or nausea Insoluble in water, is an oil at room tempera- ture. (2) Soft gelatin capsule 2.5, 5, 10 mg Absorbed 90–95% but oral bioavail- ability is 10–20% (21) Sesame oil Strickley204 Table I. Continued Molecule/ Trade Name/ Company/ Indication Chemical structure Water solubility Commercial oral formulation Excipients Dutasteride/ Avodart/ Glaxo SmithKline/ Treatment of benign prostrate hyperplasia Insoluble in water (Ref. 3, product insert, www. rxlist.com) 1. Soft gelatin capsule 0.5 mg Oral bioavailabil- ity is 40–94% (2) Mixture of mono- and diglycerides of caprylic/cap- ric acid BHT Etoposide/ VePesid/ Bristol-Myers-Squibb/ Antineoplastic Sparingly soluble in water (2) Soft gelatin capsule 50 mg Oral bioavailabil- ity is 25–75% (2) Citric acid Glycerin Water PEG 400 Isotretinoin/ Accutane/ Roche/ Antiachne Soft gelatin capsule 10, 20, 40 mg Beeswax BHA EDTA Hydrogenated soybean oil flakes Hydrogenated vegetable oils Soybean oil Itraconazole/ Sporanox/ Ortho Biotech and Janssen/ Antifungal Insoluble in water (2) Oral solution 10 mg/ml pH2 Water HP-�-CD 40% Propylene glycol 2.5% Sodium saccharin Sorbitol Flavors Lopinavir and Ritonavir/ Kaletra/ Abbott/ HIV 1. Soft gelatin capsule 133.3 mg lopina- vir and 33.3 mg ritonavir 2. Oral solution 80 mg/ml lopina- vir and 20 mg/ ml ritonavir 1. Oleic acid Polyoxyl 35 castor oil (Cremophor EL) Propylene glycol 2. Alcohol (42.2% v/v) Glycerin Polyoxyl 40 hy- drogenated cas- tor oil (Cremo- phor RH 40) Propylene glycol Sodium chloride Sodium citrate/ citric acid Water Flavors/sweeteners Solubilizing Excipients in Oral and Injectable Formulations 205 Table I. Continued Molecule/ Trade Name/ Company/ Indication Chemical structure Water solubility Commercial oral formulation Excipients Loratadine Claratin/ Schering/ Relief of allergies Not soluble in water (2) Syrup 1 mg/ml pH 2.5–3.1 Citric acid EDTA Flavor Glycerin Propylene glycol Sodium benzoate Sugar Water Nifedipine/ Procardia/ Pfizer/ Antianginal Practically insoluble in water (2) Soft gelatin capsule 10, 20 mg Glycerin Peppermint oil PEG 400 Sodium saccharin Nimodipine/ Nimotop/ Bayer/ Vasodilator Practically insoluble in water (2) Soft gelatin capsule 30 mg Glycerin Peppermint oil PEG 400 Phenobarbital/ Donnatal/ A.H. Robbins/ Anticonvulsant and sedative 1 mg/ml Elixir 3.5 mg/ml Ethanol 23% Glucose Sodium saccharin Water Progesterone/ Prometrium/ Solvay/ Hormone Practically insoluble in water (2) Soft gelatin capsule 100 mg micron- ized Peanut oil Risperidone/ Resperdal/ Janssen/ Antipsychotic Practically insoluble in water, free soluble in 0.1 N HCl (2) Oral solution 1 mg/ml Tartaric acid Benzoic acid Sodium hydroxide Water Ritonavir/ Norvir/ Abbott/ HIV Intrinsic solu- bility is 1.0 �g/ml, but the solubility increases to 400 �g/ml at pH 1 at 37°C, upon protonation of the thia- zole groups (13) 1. Soft gelatin capsule 100 mg 2. Oral solution 80 mg/ml 1. BHT Ethanol Oleic acid Polyoxyl 35 cas- tor oil (Cremo- phor EL) 2. Ethanol Water Polyoxyl 35 cas- tor oil (Cremo- phor EL) Propylene glycol Citric acid Flavors/sweet- ener/dye Strickley206 name and also shows a drug’s chemical structure, water solu- bility, the marketed formulation, and the list of excipients. Most solubilized oral formulations are either filled into gelatin capsules that range in size from 0.19–5.0 ml (15) or are oral solutions or elixirs that are usually intended for patients who cannot swallow a tablet or capsule, such as pediatric and elderly patients, or are used in dose-reduction regimens. Gelatin capsules dissolve in water, thus only the minimal amount of water is used in order to dissolve water-soluble excipients such as sweeteners and/or buffers. In addition, etha- nol is typically minimized in soft gelatin capsule formulations because ethanol can diffuse through soft gelatin films (15). Recently, there has been interest in polymer-based cap- sules, such as hydroxypropy lmethylcellulose (16,17) or poly- vinylalcohol hard capsules (18,19), in order to avoid animal- derived components and to accommodate some religious and dietary considerations. Commercially available health prod- ucts have used hydroxypropyl methylcellulose capsules since 1997, such as some of the products from Arkopharma in France (20). Injection-molded polyvinylalcohol hard capsules offer the advantages of controlled release, the ability to laser seal the cap and body, and close control of the size, shape, and dimensions of the capsule (19). To date, there appears to be no commercially available pharmaceutical products that use either hydroxypropyl methylcellulose or polyvinylalcohol capsules, but there are clinical trials ongoing of which details are not readily available. Organic Solvents in Oral Formulations Some poorly water-soluble molecules are sufficiently solubilized in solutions composed of an aqueous/organic co- solvent whereas other poorly water-so