Development and characterization of topical analgesic ointment - from laboratory to production scale

Abstract

The preparation containing methyl salicylate in an ointment dosage form, is available from various manufacturers throughout the world for the treatment of muscular pain. The limitations of the active ingredients had restricted the use of the ointment only for muscular pain. A new combination of methyl salicylate is proposed with other four active pharmaceutical ingredients (API), formulated as an ointment, that is envisaged to give wholesome benefits to the patients as it contained contemporary APIs, combined with natural products. The APIs were methyl salicylates (MS), camphor and menthol, whereas the natural products were eucalyptus oil (EO) and peppermint oil (PO). Peppermint oil contains menthol as one of the components. A proper scale-up of an ointment is very essential due to high variability of characteristics of semisolid formulation from lab scale as compared to production scale. It was also reported that due to the complex nature of the bases present in the combination of some APIs, product stability may suffer. Hence the objectives of this study were to formulate and characterize the analgesic ointment containing five APIs and identifying its critical quality attributes (CQA), to scale-up the formula from lab size to a pilot size, to develop and validate quantitative analytical method quantifying the presence of the APIs from the dosage form, to identify and optimize critical processing parameters (CPP) for the scale-up batches and finally to conduct the accelerated and real-time stability studies for the scale-up batches. Briefly, the lab scale was formulated from 100g to 5kg batch size, consisting of 25% w/w MS, 5% camphor, 5% menthol, 5% EO and 5% PO, by using the overhead stirrer (100 rpm and 15 mins of mixing time). Different formulations were tested by varying the ratio between the two types of ointment bases, namely, petroleum jelly (PJ) and beeswax (BW). It was found that this lab scale gave the pH between 4.83 to 4.93, the hardness between 31.33 to 35.00g, the viscosity between 558 to 2803 mPa.s and the spreadability from 75 to 1947 mPa.s. The ointment exhibited pseudoplastic behaviour with yield stress and was found to be thixotropic. Three formulations consisted of ratios PJ: BW 10:90 (FI), 30:70 (FII) and 50:50 (FIII) were selected to be scaled-up and characterized. The scaled-up was conducted using a vacuum homogenous mixer and automatic tube filling machine for 35kg batch size. It was identified at this stage that the CPPs of vacuum homogeneous mixer were temperature of mixing and cooling, speed of the agitator and the time of mixing. While, CPPs of automatic tube filling machine were dosage and speed. Critical quality attributes (CQA) were identified as physical characteristic, minimum fill, content based on assay and microbial limit test. The formulations FI to FIII were characterized and exhibited pH range from 4.75 to 4.95, viscosity of 735 to 1670 mPa.s and spreadability of 735 to 1670 mPa.s. The ointment exhibited pseudoplastic behaviour with yield stress and found to be thixotropic. By using gas chromatography coupled with flame iodide detector (GC-FID), analytical method was developed and validated using the scale-up batches and all parameters namely specificity, limit of quantification (LOQ), linearity and range, precision and recovery, and intermediate precision fulfil the specification. After storage up to 6 months, the percentage content of MS, camphor, menthol, EO and PO were 24.6 to 25.9% w/w, 4.6 to 4.8% w/w, 6.8 to 7.5% w/w, 4.95 to 5.2% w/w and 6.85 to 7.1% w/w respectively. Hence, we conclude that a stable ointment consisted of five APIs had been successfully formulated and scaled-up. The predicted shelf life was 2.1 years.