Assessing the impact of nimodipine devitrification in the ternary cosolvent system through quality by design approach

Nimodipine (NM) commercial formulation has been recalled due to drug crystallization in the product. Aim of present investigation was to systematically evaluate NM ternary cosolvents systems, characterize the crystallized drug and develop discriminating dissolution method that could detect the drug crystallization in the product. Mixture design was constructed using independent components namely water (X1), glycerin (X2) and polyethylene glycol 400 (X3, PEG-400). Nineteen formulations were developed using various level of cosolvents mixture while drug concentration was kept constant. The response selected was the drug crystallized in the formulations kept at four storage conditions 5 °C, 15 °C, 25 °C and 25 °C/60% RH for four weeks. The crystallized drug was characterized by Fourier transformed infrared (FTIR), near infrared (NIR), NIR-chemical imaging and Raman spectroscopies, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy. Dissolution of formulation and modification was tested by USP method 2 in 0.25 and 0.50% sodium lauryl sulphate (SLS) aqueous media and run at 50 and 75 rpm. X1 promoted drug crystallization at all conditions of storage and reverse was true for X3. Characterization data indicated that the crystallized drug in most of the formulations were modification II, but a few formulations contained significant proportion of the modification I. Dissolution in 0.25% (w/v) SLS at 75 rpm was more discriminating in detecting the crystallization in the product compared to dissolution in 0.5% (w/v) SLS media. In summary, cosolvents system of NM was prone to crystallization depending upon the cosolvents composition and storage conditions. A more rational approach to develop NM formulation would entail a then through understanding of the causes of crystallization and their characterization in a variety of storage conditions.

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