Preparation of Microcrystals of Piroxicam Monohydrate by Antisolvent Precipitation via Microfabricated Metallic Membranes with Ordered Pore Arrays.

Rahimah Othman,Goran T Vladisavljević,Zoltan K Nagy,Elena Simone,Richard G Holdich

doi:10.1021/acs.cgd.7b01307

Rahimah Othman, Goran T Vladisavljević + Show 3 more

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https://doi.org/10.1021/acs.cgd.7b01307

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Abstract

Microcrystals of piroxicam (PRX) monohydrate with a narrow size distribution were prepared from acetone/PRX solutions by antisolvent crystallization via metallic membranes with ordered pore arrays. Crystallization was achieved by controlled addition of the feed solution through the membrane pores into a well-stirred antisolvent. A complete transformation of an anhydrous form I into a monohydrate form of PRX was confirmed by Raman spectroscopy and differential scanning calorimetry. The size of the crystals was 7–34 μm and was controlled by the PRX concentration in the feed solution (15–25 g L–1), antisolvent/solvent volume ratio (5–30), and type of antisolvent (Milli-Q water or 0.1–0.5 wt % aqueous solutions of hydroxypropyl methyl cellulose (HPMC), poly(vinyl alcohol) or Pluronic P-123). The smallest crystals were obtained by injecting 25 g L–1 PRX solution through a stainless-steel membrane with a pore size of 10 μm into a 0.06 wt % HPMC solution stirred at 1500 rpm using an antisolvent/solvent ratio of 20. HPMC provided better steric stabilization of microcrystals against agglomeration than poly(vinyl alcohol) and Pluronic P-123, due to hydrogen bonding interactions with PRX and water. A continuous production of large PRX monohydrate microcrystals with a volume-weighted mean diameter above 75 μm was achieved in a continuous stirred membrane crystallizer. Rapid pouring of Milli-Q water into the feed solution resulted in a mixture of highly polydispersed prism-shaped and needle-shaped crystals.

Highlights

IntroductionLow aqueous solubility of active pharmaceutical ingredients (APIs) is a major problem in the design of pharmaceutical dosage forms.[1−3] Over 60% of APIs fall under BCS Class II (low solubility and high permeability) or Class IV (low solubility and low permeability)
Low aqueous solubility of active pharmaceutical ingredients (APIs) is a major problem in the design of pharmaceutical dosage forms.[1−3] Over 60% of APIs fall under BCS Class II or Class IV
Crystallization was achieved by controlled addition of the feed solution through the membrane pores into a well-stirred antisolvent

Summary

Introduction

Low aqueous solubility of active pharmaceutical ingredients (APIs) is a major problem in the design of pharmaceutical dosage forms.[1−3] Over 60% of APIs fall under BCS Class II (low solubility and high permeability) or Class IV (low solubility and low permeability). The surface area of drug substances can be increased by mechanical milling,[7] high pressure homogenization,[8] and spray drying.[9] these techniques require high energy inputs and expensive equipment, and often lead to a broad particle size distribution, thermal degradation, heterogeneous particle shapes, and poor batch-to-batch reproducibility.[3,4,10] Antisolvent precipitation/crystallization is an alternative approach to prepare fine drug particles.[11,12] The technique is simple and does not require elevated temperatures, high energy inputs, and Class 1 solvents.[13−17] It has been used to prepare ultrafine powders and micro-/nanodispersions of many APIs, including budesonide,[18] danazol,[19] beclomethasone dipropionate,[20] griseofulvin and fenofibrate,[21] salbutamol sulfate,[22] prednisolone,[23] atorvastatin,[24] L-glutamic acid,[25] and paracetamol.[26]

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