The importance of impurity on pharmaceutical processes

Solution crystallization processes are widely treated as binary systems consisting of a solute and a solvent. For real systems, additional components such as additives and impurities may significantly impact crystallization processes even when present in very small amounts. An understanding of the mechanistic role of additives and impurities is therefore essential to design and control crystallization processes. This thesis first describes the solubility and crystallization of pure active pharmaceutical ingredients (API’s) from solution. Subsequently, it discusses the thermodynamic, kinetic and crystallization effects, caused by impurities. Eventually, these knowledge were applied to optimize impurity removal processes by using a combined experimental-modelling approach to investigate a mother-liquor recycle operation and improve properties on the processability of API. The gravimetric solubility method and how solubility models cope with industrially-relevant complex products belonging to the α-Thio-β-chloroacrylamide family which is a class of highly versatile synthetic intermediates was examined. One of the drawbacks of the gravimetric method is the evaporation of solvents which is due to elevated operating temperature or the volatile nature of the solvent itself. Solubility data at higher temperatures, beyond the atmospheric boiling point of solvents, allows for an increase in crystallization yield. A pressurized-synthetic methodology was presented as a new technique for determining high-temperature solubility data even beyond the atmospheric boiling point. With the gravimetric method in combination with HPLC analysis, the effect of impurities (4-nitrophenol and 4’-chloroacetanilide) on the solubility of paracetamol has been determined and modelled. To study the effect of volume on the nucleation kinetics of paracetamol, an automated FBRM-method was applied to record induction times. The shear rate was rationalized to be the part of the kinetic parameter that changes most significantly when changing the crystallizer type, up to a specific volume beyond which the effect becomes negligible. Induction time experiments were used in combination with the classical nucleation theory and demonstrated that the impurities employed reduced the nucleation rate. The impurities did not affect the solid−liquid interfacial energy but significantly reduced the kinetic factor. The poor compression ability of paracetamol is well known. The crystal habit of paracetamol was altered in the present of structurally similar impurity (4’-chloroacetanilide) to improve the compaction behaviour of the paracetamol crystals. An experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. As a result, it was feasible to accurately control the compressibility and the amount of 4’-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the solvent for crystallization. In crystallization process, recycle of mother liquor allows for reduced waste and increased yield with complete control of the impurity concentration. A sequence of batch-cooling crystallization experiments was demonstrated to investigate how a mother liquor recycle operation affects the crystallization of paracetamol as a result of the gradual build-up of the impurity 4-nitrophenol. The results can be used as a guide to estimate the optimum mother liquor recycle conditions that would lead to reduced product and solvent waste and improved process efficiency. The result of this thesis addresses a number of challenges in the crystallization of API’s and impurities and leads to improved impurity removal processes. To obtain high yield as well as specific crystal quality attributes while maintaining a control on impurities, techniques strategies including continuous crystallization with recycle and pressurized methods were developed. Furthermore, rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications

Thermodynamic properties of paracetamol impurities 4-nitrophenol and 4'-chloroacetanilide and the impact of such impurities on the crystallisation of paracetamol from solution

The impact of structurally-related additives and impurities on active pharmaceutical ingredients is an essential yet poorly understood area. This work describes the characterisation of temperature-dependent solid-liquid properties of 4-nitrophenol and 4′chloroacetanilide in four different alcohols and their effect as impurities on the crystallisation of paracetamol. The solubility of 4-nitrophenol appeared to be significantly higher than paracetamol whereas the solubility of 4′chloroacetanilide was lower than paracetamol. The solubility difference between the impurities could be rationalised based on their molecular structure and hydrogen bonding interactions. The solubility data was modelled using empirical and thermodynamic models. Recrystallisation of paracetamol from solutions containing the highly soluble 4-nitrophenol impurity resulted in small uniformly sized high purity paracetamol crystals whereas the presence of the poorly soluble 4′chloroacetanilide impurity induced the formation of large needle shaped crystals of paracetamol. These differences in crystallisation are a consequence of the solubility difference and the different functional groups of paracetamol and its impurities. Overall this study serves as fundamental information for the development of crystallisation approaches for the purification of paracetamol from its main impurities

Organic salts of pharmaceutical impurity ρ-Aminophenol

The presence of impurities can drastically affect the efficacy and safety of pharmaceutical entities. ρ-Aminophenol (PAP) is one of the main impurities of paracetamol (PA) that can potentially show toxic effects such as maternal toxicity and nephrotoxicity. The removal of PAP from PA is challenging and diffi cult to achieve through regular crystallization approaches. In this regard, we report four new salts of PAP with salicylic acid (SA), oxalic acid (OX), l-tartaric acid (TA), and (1S)-(+)-10-camphorsulfonic acid (CSA). All the PAP salts were analyzed using single-crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The presence of minute amounts of PAP in paracetamol solids gives a dark color to the product that was diffi cult to remove through crystallization. In our study, we found that the addition of small quantities of the aforementioned acids helps to remove PAP from PA during the filtration and washings. This shows that salt formation could be used to efficiently remove challenging impurities

Tailoring crystal size distributions for product performance, compaction of paracetamol

Paracetamol crystals often exhibit poor compressibility properties, which results in capping issues. The Particle Size Distribution (PSD) of paracetamol was engineered to improve the compressibility of paracetamol crystals. This was accomplished by growing paracetamol crystals in the presence of additives. The active pharmaceutical ingredient Phenacetin and impurity 4-chloroacetanalide were used to modify the crystal properties of paracetamol. In solution, the phenacetin or 4-chloroacetanalide molecules adsorb onto the paracetamol crystal faces selectively (110 or 011) and inhibit the further growth of the paracetamol crystal and consequently, the paracetamol crystal growth is reduced substantially. For controlling the PSD of crystal to improve the compressibility of paracetamol crystals, a set of cooling crystallization experiments in the presence of additive was designed. According to a statistical experimental design, the cooling rate was the most effective parameter. The PSD was reduced when paracetamol crystallized from the controlled crystallization in the presence of less than 3 mol% of both additives. These smaller particles increased almost fourfold the compressibility of paracetamol in comparison to the commercial material. Moreover, tablets were prepared for each formulation using a direct compaction method. The results illustrated that a higher tablet hardness of paracetamol was achieved by tailoring the paracetamol crystal size distribution. In addition, the tablet disintegration time was higher for the formulation increased hardness. Overall, this work presents the potential use of structurally similar compounds as additives to alter the mechanical properties of an API

Effects of scale-up on the mechanism and kinetics of crystal nucleation

Insight into nucleation kinetics and other nucleation parameters can be obtained from probability distributions of induction time measurements in combination with the classical nucleation theory. In this work, induction times of crystallization were recorded using a robust and automated methodology involving a focused beam reflectance measurement probe. This methodology is easily interchangeable between different crystallizers which allowed us to investigate the effects of scale-up on the kinetics of crystal nucleation of paracetamol from 2-propanol in four different crystallizers, ranging from small magnetically stirred 10 mL solutions to overhead-stirred solutions of 680 mL. The nucleation rate was an order of magnitude faster in the magnetically stirred crystallizer as compared to the crystallizers involving overhead stirring. The thermodynamic part of the nucleation rate expression did not significantly change the nucleation rate, whereas the kinetic nucleation parameter was found to be the rate-determining process when the crystallization process was scaled-up. In particular, the shear rate was rationalized to be the part of the kinetic parameter that changes most significantly when the crystallization process was scaled-up. The effect of shear rate on the nucleation kinetics decreases with increasing volume and plateaus when the volume becomes too large. In this work, the nucleation mechanism was also investigated using the chiral sodium chlorate system. These experiments showed that the single nucleus mechanism is the underlying nucleation mechanism in all four tested crystallization setups when supersaturation remains the same. When the supersaturation was changed continuously through cooling, crystallization was driven by a multinucleus mechanism. The automated and robust method used to measure induction times can easily be extended to other crystallizers, enabling the measurement of induction times beyond small crystallizer volumes