Crystallization Engineering of Ibuprofen for Pharmaceutical Formulation

Crystallization is a widely used unit operation in the pharmaceutical and chemical industries. In the last three decades in the pharmaceutical industries this has led to a new direction for directly crystallizing Active Pharmaceutical Ingredients (APIs) to have a suitable product size and this is the focus of this work. The model drug used in this study was racemic ibuprofen, commonly known as “ibuprofen” which is a very popular analgesic. Ibuprofen was also chosen as little crystallization kinetics information was available in the published literature and there is potential industrial interest in crystallizing this material. Ibuprofen is mostly supplied in tablet form. However, commercially available ibuprofen particles are needle like with rough surfaces and show poor flowability, poor compaction behavior and a tendency to stick to the tablet punches. To overcome these problems, a suitable size and shape of ibuprofen crystal is desirable that could be directly compressed with fewer operation steps (usually from 6 down to 2) but still having good product stability and therapeutic efficacy. A controlled crystallization process would be useful in producing such particles. This project was aimed to develop a controlled crystallization process for ibuprofen (I) crystallized from absolute ethanol (E) or water - ethanol mixtures (W+E) to explore conditions favorable for industrial crystallization and to gain knowledge of its solubility, metastability, nucleation and crystal growth kinetic data that is essential in the design of industrial crystallizers. The experimental data of this study were all obtained at conditions in line with expected industrial practice which includes temperatures between 10oC to 40oC. Solubility measurement data shows that the ibuprofen solubility in ethanol increases significantly with temperature from 0.59 g/g at 10oC to 2.14 g/g at 40oC (as mass ratio unit I/E). The data was fitted by a square law relation, I*/E = 0.497 (± 0.008) + 0.001026 (± 0.000012) T2, where T is temperature in oC, I*/E is the solubility mass ratio of ibuprofen to ethanol in solution and the values in brackets are the 95% confidence uncertainties on the parameters. For aqueous ethanol, adding water initially slightly increases the solubility at 25 and 40oC, but then it decreases substantially. At 40oC solutions between 34% to 64% mass fraction water in solvent W/(W+E) separate into two liquid phases. The upper layer, with the lower density, contains the higher ibuprofen and ethanol contents. The metastable zone width (MSZW) in alcoholic solutions is quite narrow. For ethanol solutions, the 1 hour secondary nucleation threshold MSZW, measured as relative supersaturations, range from 0.03 to 0.08. For water - ethanol mixtures it ranges from 0.001 to 0.02. The primary nucleation thresholds MSZW are approximately six times greater. These nucleation thresholds were used to select metastable zone operating conditions for the nucleation and crystal growth rate experiments of this thesis. To develop a continuous crystallizer, nucleation kinetics data are necessary. Measurements were made of the secondary nucleation rates for ibuprofen in ethanol and water - ethanol mixtures using a batch technique. The nucleation rate appears to be first order with respect to supersaturation and to be independent of temperature with a nucleation rate constant, kB = 1.73×108 (± 65%) #/min/(kg slurry)/(unit of ∆(I/E)). It appears to fall with increasing water content in aqueous solutions. Further work is needed in this area. Seeded batch experiments were used to measure ibuprofen crystal growth rates at similar range of conditions. Ibuprofen shows growth rate dispersion (GRD), so size proportional growth (SPG) seeds having a coefficient of variation by volume CVV of 0.50 (± 0.03), prepared from a batch nucleation, were used. For the effect of supersaturation s, the data was fitted with a power law expression, G = kG sn. It was found that growth rates were first order, i.e. n = 1. For n = 1, the best fit kG value is 15 (± 10%) μm/min/unit of (I/E) at 25oC for crystals having the volume median size. The error is the 95% uncertainty. kG increases with temperature with an activation energy of 13.7 (± 18%) kJ/mole. Thus growth appears to be kinetics controlled rather than mass transfer controlled. In the chosen supersaturation units, kG increases with increasing water content in aqueous mixtures. Combining the effects gave the correlation for kG = 5.3 (± 3.1) *exp{0.024 (± 0.015)*T}* exp[{7.2 (± 2.0) – 0.21 (± 0.1)*T} *XW]. where T is the temperature in °C, XW is the mass fraction of water to ethanol in solution and the values in brackets are the 95% confidence uncertainties on the parameters. The shape of the crystals from all solutions were plate like and were of good size. Sample calculations are provided to illustrate how the data obtained can be used in the process design of crystallizers to produce crystals of the desired size.