Abstract
Conversion into the amorphous form enhances the dissolution of poorly soluble drugs, however the barrier to market for medicines containing an amorphous drug is poor stability. The aim was to produce the amorphous form of a drug within a capsule, without thermal or mechanical stress during manufacture. To facilitate this aim, the mechanism for drug-polymer interaction was explored. Nifedipine and polyvinylpyrrolidone were dissolved in tert-butanol at different drug/polymer ratios. These solutions were dispensed into gelatin capsules and freeze-dried. Differential scanning calorimetry (DSC) & novel FT-IR analysis based on peak symmetry measurements confirmed the absence of crystallinity when polyvinylpyrrolidone exceeded 50%w/w. Capsules containing 10 mg of nifedipine were amorphous and stable for over 3 months at ≈40 °C. Evidence of hydrogen bonding between the N-H group of nifedipine and the C=O group of PVP was observed and this interaction inhibited nifedipine crystallisation. PVP’s high affinity for water and the nifedipine-polymer interaction lead to a significant dissolution rate enhancement. The freeze-dried capsule, 10%w/w nifedipine/PVP, had the highest dissolution rate constant of 0.37 ± 0.05 min−1, and the lowest time to achieve 50% dissolution or t1/2 of 1.88 ± 0.05 min. This formulation reached 80% dissolved in less than 6 min whereas the equivalent marketed liquid filled nifedipine capsule took 3 times longer to reach 80% dissolution.
Highlights
The biopharmaceutical classification system (BCS) ranks drugs in accordance to their solubility and permeability[1], the dominating factors that influence the oral bioavailability of drugs[2, 3]
Collapse was avoided within the capsules by maintaining a product temperature (Tp) 5 °C below the lowest the freeze concentrated solutions (Tc) during the primary drying cycle
Other organic solvents that can enable the dissolution of NIF and PVP, such as ethanol and DMSO, may be used in formulating amorphous nifedipine in PVP, the physicochemical properties of TBA, for example its vapour pressure of 35.72 mbar below its freezing point, allows TBA to be removed during a freeze drying cycle
Summary
The biopharmaceutical classification system (BCS) ranks drugs in accordance to their solubility and permeability[1], the dominating factors that influence the oral bioavailability of drugs[2, 3]. Class II BCS, drugs with high permeability but low solubility, form a large number of the lead compounds generated by pharmaceutical research, but their low oral bioavailability reduces class II’s developability into medicines[4]. Due to limited aqueous solubility, the absorption of class II BCS drugs is hindered[1]. This may be improved through formulation strategies, for example rendering the drug into its amorphous form[3, 5]. Water is the principle solvent used for freeze-drying[18] which puts PWSD’s at a disadvantage, as acceptable concentrations of the PWSD in the aqueous feed solutions are impossible to achieve. Conventional hard gelatin capsule shells are the perfect vessel to use, assuming they withstand liquid loading and freeze-drying
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