Solid-State Techniques for Improving Solubility

Abstract

Poor aqueous solubility of a drug substance can often be attributed to strong intermolecular forces within its crystal lattice which, in turn, prevent molecules from escaping in solution. Through the use of solid-state chemistry, it is possible to modify the crystal structure in such a way that mitigates intermolecular forces, thus improving aqueous solubility and increasing rates of dissolution. Solid-state techniques utilized for solubility enhancement include the formation of salts, polymorphic or amorphous forms, and co-crystals. Each technique has specific advantages and, in some cases, disadvantages that may prevent its successful use. The purpose of this chapter is to describe each of the methods, allowing the reader to gain an understanding of solid-state modifications available for solubility enhancement.

Appendices

Method Capsule 1Preparation of Amorphous Solids - Spray-Drying

Based on the method reported by Kim et al. (2008).

• Objective

• To obtain an amorphous drug substance by the spray-drying technique

Equipment and Reagents

• Atorvastatin calcium

• Acetone or tetrahydrofuran

• Laboratory-scale spray-dryer

Method

• Dissolve atorvastatin calcium in acetone or tetrahydrofuran at a concentration of 100 mg/mL.

• Set the drying air flow rate to 0.70 m³/min.

• Set the inlet temperature of the spray dryer to 70°C.

• Feed the solution into the spray dryer at 3 mL/min with an atomization pressure of 10 kPa.

• Ensure that the outlet temperature is in the range of 62–65°C.

• Collect the dried powder.

Results

• Laser diffraction analysis revealed that the particle size of atorvastatin calcium spray-dried from acetone and tetrahydrofuran was 3.62  ±  0.15 μm and 7.31  ±  0.21 μm, respectively.

• BET specific surface area analysis demonstrated that the surface area of atorvastatin particles spray-dried from acetone and tetrahydrofuran was 3.69  ±  0.06 m²/g and 0.95  ±  0.03 m²/g, respectively. The specific surface area of unprocessed material was 14.56  ±  0.17 m²/g.

• Differential scanning calorimetry and X-ray diffraction analyzes indicated that all spray-dried material lacked crystalline character and was amorphous.

Method Capsule 2Preparation of Amorphous Solids - Supercritical Anti-solvent Processing

Based on the method reported by Kim et al. (2008).

Objective

• To obtain an amorphous drug substance by supercritical anti-solvent (SAS) processing.

Equipment and Reagents

• Atorvastatin calcium

• Acetone or tetrahydrofuran

• Laboratory-scale supercritical anti-solvent processor

• Carbon dioxide (CO₂)

Method

• Deliver CO₂ into particle formation vessel equilibrated at 40°C until the pressure reaches 12 MPa.

• Dissolve atorvastatin calcium in acetone or tetrahydrofuran at a concentration of 100 mg/mL.

• The drug solution and supercritical CO₂ were co-injected through a two-flow nozzle at 0.5 g/min and 45 g/min, respectively.

• After the drug solution was exhausted, fresh CO₂ was cycled into the vessel to remove residual solvent at 45 g/min.

Results

• Laser diffraction analysis revealed that the particle size of SAS-processed atorvastatin particles from acetone and tetrahydrofuran was 68.7  ±  15.8 nm and 95.7  ±  12.2 nm, respectively. Particle size of the unprocessed material was 3.83  ±  0.08 μm.

• BET-specific surface area analysis demonstrated that the surface area of SAS processed atorvastatin particles from acetone and tetrahydrofuran was 120.35  ±  1.40 m²/g and 79.78  ±  0.93 m²/g, respectively. The specific surface area of unprocessed material was 14.56  ±  0.17 m²/g.

• Differential scanning calorimetry and X-ray diffraction results indicated that all spray-dried material lacked crystalline character and was amorphous.

Method Capsule 3Preparation of Amorphous Solids - Melt Quenching

Based on the method reported by Hancock and Parks (2000).

Objective

• To obtain an amorphous drug substance by melt quenching.

Equipment and Reagents

• Indomethacin

• Liquid nitrogen

Method

• Heat indomethacin to a temperature that induces melting (∼160°C).

• Quench the melt with liquid nitrogen such that indomethacin solidifies.

Results

• Differential scanning calorimetry and X-ray diffraction results indicated that melt-quenched material lacked crystalline character and was amorphous.

Method Capsule 4Preparation of Co-crystals - Temperature-Induced Precipitation

Based on the method reported by Hickey et al. (2007).

Objective

• To obtain a co-crystal of carbamazepine and saccharin by temperature-induced precipitation.

Equipment and Reagents

• Carbamazepine

• Saccharin

• Ethanol

• Methanol

• Water-jacketed glass crystallization vessel

Method

• Anhydrous carbamazepine (0.089 mol) and saccharin (0.089 mol) were ­combined in the crystallization vessel.

• Solids were dissolved in 280 mL of a 62.5/37.5% (v/v) ethanol/methanol, mixture and heated to 70°C for 1 h under reflux.

• Temperature was decreased in 10°C increments while stirring to induce precipitation.

• Following equilibration at 30°C, solids were isolated using a Buchner funnel and rinsed with cold ethanol.

• The resulting powder was air-dried.

Results

• A product yield of 76% was obtained.

• Microscopy studies showed that the particle size of the crystals was between 500 and 1,000 μm.

• X-ray powder diffraction and differential scanning calorimetry studies demonstrated that a single polymorphic co-crystal form was prepared.

Method Capsule 5Preparation of Co-crystals - Seed-Induced Precipitation

Based on the method reported by McNamara et al. (2006).

Objective

• To obtain co-crystals of a new drug candidate (compound 1) with glutaric acid by seed-induced precipitation.

Equipment and Reagents

• Compound 1

• Glutaric acid

• Chloroform

• Water-jacketed glass crystallization vessel

Method

• Compound 1 (8.431 mmol) and glutaric acid (8.410 mmol) were dissolved in boiling chloroform with stirring.

• The solution was concentrated by continued boiling until the volume was 50 mL.

• Co-crystal seeds (generated in thermal experiments) were introduced into the hot solution.

• After crystallization began, the solution was cooled over a 15 min period.

• Approximately 100 mL of cyclohexane was added and the solution was cooled on ice for 30 min.

• The co-crystal was isolated by filtration.

• The resulting powder was air-dried.

Results

• A product yield of 92% was obtained.

• The volumetric median diameter D_v(0.5) and that of the 90th percentile D_v(90) were found to be 49 μm and 131 μm, respectively.

• X-ray diffraction analysis showed a unique pattern that was distinguished from compound 1 and glutaric acid.

• Differential scanning calorimetry experiments indicated that the co-crystal exhibited a melting point different from that of compound 1 or glutaric acid.

Method Capsule 6 Preparation of Co-crystals - Grinding

Based on the method reported by Trask et al. (2004)

Objective

• To obtain co-crystals of caffeine and glutaric acid by a solid-state grinding technique.

Equipment and Reagents

• Anhydrous caffeine

• Glutaric acid

• Optional non-polar solvents: n-hexane, cyclohexane, or heptane

• Optional polar solvents: chloroform, dichloromethane, acetonitrile and water

• Ball grinder/mill

Method

• Equimolar amounts of caffeine and glutaric acid were combined in a stainless steel grinding jar.

• Optional: Add four drops of either a non-polar solvent or a polar solvent.

• Grind the materials together.

• Allow any residual solvent to evaporate.

Results

• X-ray diffraction analysis demonstrated that co-crystals were formed when the material was prepared in the absence of solvent and with non-polar or polar solvents.

• Form I of the co-crystal was found to form when no solvent or a non-polar solvent was used.

• Form II was predominantly formed when a polar solvent was used.