Efavirenz pre-formulation study : selection of a cyclodextrin inclusion complex or co-crystal complex for tabletting
Efavirenz is a non-nucleoside reverse transcriptase inhibitor used as an anti-retroviral for the treatment of human immunodeficiency virus (HIV) type I. It is classified as a class IΙ drug under the Biopharmaceutical Classification System (BCS) and exhibits a low solubility (aqueous solubility of 9.0 μg/ml) and high permeability (variable oral bioavailability). This study aims to choose a pre-formulation protocol with the best efavirenz derivative in literature between co-crystals and CD inclusion complexes. Upon selection of the efavirenz derivative, the complications of both small scale and large scale laboratory pre-formulation production is highlighted for formulation of a tablet dosage form. Numerous variables were selected for the pre-formulation protocol. Physical, chemical, pharmacological, pharmaceutical and economical variables were investigated. Citric acid monohydrate (CTRC) was chosen as the best co-former for a co-crystal while hydroxypropyl-beta-cyclodextrin (HP-β-CD) was selected as a host for an inclusion complex. Pharmaceutically, the angle of repose, Carr’s index, Hausner’s ratio, moisture content, disintegration time, hardness/resistance to crush, manufacturing process problems and particle size of the CTRC and HP-β-CD were all evaluated. The CTRC was ultimately selected for formulation of a tablet. The preparation of small laboratory scale of EFA/CTRC co-crystal was successfully achieved after several attempts. The large laboratory scale of EFA/CTRC was prepared under various environmental seasons which were indicated as batches 1-6 for purposes of this study. Characterization of the large laboratory scale EFA/CTRC co-crystals was performed by scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and by physical inspection (i.e. season, texture, colour, shape and particle size) of the EFA/CTRC product. Batch 1 and 2 were prepared during the summer season. The SEM analysis showed that the particles were needle-like shaped. The thermal analysis values of batch 1 by HSM, DSC and TGA results were 123 °C, 119 °C and 1.68 % of mass loss, respectively. In batch 2, morphology results by SEM revealed spikes of irregular and agglomerated particles. Batch 2 melted at 123 °C and a small unmelted quantity was observed at 143 °C. The DSC and TGA (mass loss) analysis were 118 °C and 0.75 % respectively. The hardness test of EFA/CTRC tablet prepared in batch 2 was extremely hard hence failed the disintegration test. The EFA/CTRC prepared in batches 3, 4 and 5 was during the winter season which is associated with high humidity and wet weather conditions. The SEM, DSC, TGA results were significantly different from the previous batches. The SEM morphology was highly irregular particles for batch 3, clustered and randomly size particle for batch 4 and irregular, needle-like, spikes and spherical shaped particles for batch 5, respectively. The thermal results HSM, DSC and TGA confirmed the presence of moisture in the prepared EFA/CTRC products. The HSM melting point results of batches 3, 4 and 5 were 123 °C, 115 °C and 121 °C, respectively. The DSC results of 110 °C, 105 °C and 118 °C were observed for batches 3, 4 and 5 respectively. The mass loss i.e. TGA results for batches 3, 4 and 5 were 1.178%, 1.5 % and 2.235 % respectively. In batch 6, EFA/CTRC was prepared using a different commercial batch of EFA and CTRC. The SEM results indicated the formation of needle-like and clustered particles. The values obtained from HSM, DSC and TGA results were 124 °C, 114 °C and 0.54 % in mass loss. The physical appearance of EFA/CTRC prepared from batch 1 and 2 were white in colour while batch 3, 4, 5 and 6 of the prepared EFA/CTRC was pink in colour. The physical appearance of the individual batches differed but the identity of the sample remained intact implying the same pharmacological effects with differing pharmaceutical properties impacting the dosage form preparation.
Efavirenz, Co-crystallization, Cyclodextrin inclusion, Scanning electron microscopy, Hot-stage microscopy
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