Cooling Crystallization of Paracetamol in Hollow Fiber Devices

Abstract

We examine here cooling crystallization of aqueous paracetamol solutions in hollow fiber devices. It is shown that a solid hollow fiber crystallizer (SHFC)-static mixer assembly can be operated successfully up to 30-40°C below the metastable zone limit. Such a capability is not existent in industrial cooling crystallizers; it allows the decoupling of nucleation and growth, an opportunity offered currently only by impinging jet mixers for antisolvent crystallization. In addition, it leads to the achievement of very high nucleation rates and hence small crystal sizes. The former were 2-4 orders of magnitude higher than values previously obtained in solid hollow fiber crystallizers for potassium nitrate and salicylic acid and reached values encountered only in impinging jet crystallization. A qualitative comparison with existing literature data showed that the SHFCstatic mixer combination confined the crystal size distribution (CSD) to smaller sizes and a narrower range. Finally, a linear relationship between the mean crystal size and the cooling medium temperature was observed. This relationship is indicative of the simplicity available in SHFCs vis-à-vis CSD control. IntroductionCrystallization and precipitation processes are often the most critical step in the separation, purification, and production of active pharmaceutical ingredients (APIs) and fine chemicals. The most important product characteristics such as crystal size distribution (CSD), crystal shape, and habit are solely determined by the operating conditions during the crystallization step (i.e., temperature, rates of supersaturation generation and depletion, mixing, and agglomeration/breakage phenomena). Good control of the above parameters can yield a product of acceptable and reproducible quality. In addition, downstream processing such as filtration and drying can benefit significantly in terms of robustness, operating simplicity, and cost-effectiveness from a well-designed and controlled crystallization process.Cooling crystallization from solution is probably the most frequently employed crystallization technique in the pharmaceutical industry. It is carried out in stirred vessels operated in a batch or continuous mode. The former is by far the predominant practice in the pharmaceutical industry; the latter is mainly employed in the production of inorganic chemicals. 1 Despite the fact that industrial crystallizers can be successfully operated, there is often considerable variability in the principal process outcome, the crystal size distribution. Moreover, they cannot in general meet the targets of a narrow CSD and a small mean crystal size, often desirable in the production of pharmaceuticals and specialty chemicals, due to imperfect mixing and the resulting non-uniform supersaturation conditions inside the crystallizer. Imperfect mixing is an inherent characteristic of industrial crystallizers whose performance is often different from that obtained at laboratory scale and frequently characterized by segregation effects. 2 Imperfect mixing is a...

Hydroxypropyl Methylcellulose as a Novel Tool for Isothermal Solution Crystallization of Micronized Paracetamol

“…Zarkadas &Sirkar 18 have found that a combination of homogeneous and heterogeneous nucleation is possible in a cooling crystallisation process of Paracetamol in water at high supersaturation ratios, i.e. S =3 and above, which was the case in this present study.…”

“…Nevertheless, with the presence of HPMC in the crystallisation solution the nucleation became increasingly limited as more polymer additive is added to the solution. This was explained by Zarkadas&Sirkar 18 and Tian et al 24 based on inter-molecular 12 hydrogen bonding between Paracetamol and the polymer additive. HPMC has both a hydrogen bonding donor and acceptor groups on its ring structure ( Figure S2), therefore showing a high Hbonding ability and network association with drug molecules as concluded from FT-IR results of Tian et al 24 Similar conclusion was obtained by Sahoo et al 25 using Raman spectroscopy.…”

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“…However, experimental results were not presented in the paper. Figure 9 The arrangement of alternate layers of Kapton ® within the recuperator to form a counter flow heat exchanger 62 Using hollow fibres for creation of uniform temperature in a constrained environment of submillimetre scale, a new cooling crystallization technique dedicated for pharmaceutical industry was proposed by Zarkadas and Sirkar 39 . This technique was tested successfully for both aqueous (KNO3) and organic system (salicylic acid in ethanol) with a high solubility.…”

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“…To ensure the accuracy of particle sizes, the contour line of individual crystal or each particle was manually drawn, followed by the automatic measurement of the area. By assuming the crystal as an ellipse, 20 the circle equivalent diameter (CED) was calculated, which is regarded as the crystal size in this study. At least 300 crystals were measured for each run to ensure the statistical significance of the acquired crystal size distribution.…”

“…Owing to the solubility change, the excess dissolved salt crystallizes and precipitates out from the supersaturated solution at a high rate. This technology has been tested successfully for both low solubility systems such as paracetamol in water 20 and high solubility systems such as KNO 3 in water and salicylic acid in ethanol. 21 The combination of fast cooling via SHFCC (e.g., 20−30 °C/s) and the downstream mixer also realized the successful operation of paracetamol crystallization at 30−40 °C below the metastable zone limit.…”