Process analytical technology based monitoring and control of crystal properties in pharmaceutical crystallisation processes.

Crystallization is an important unit operation used in a variety of industries. Its importance in the pharmaceutical industries is due to a large number of active pharmaceutical ingredients that are utilised in solid form. It is estimated that more than 80% ofpharmaceutical products involve at least one crystallization step in their manufacturing process (Reutzel-Edens, 2006). The pharmaceutical crystallisation operation is often critical because it determines the product properties, such as the crystal size distribution, morphology and polymorphic form. These properties in tum influence the efficiency of the subsequent downstream operations, particularly filtration and drying. The properties also affect the therapeutic performance ofthe product, such as dissolution rate and bioavailability. A proper control of crystallization processes offers possibilities for improved process efficiency and better product qualit

Seeded batch cooling crystallization with temperature cycling for the control of size uniformity and polymorphic purity of sulfathiazole crystals

An experimental study has been conducted to evaluate the capability of a seeded batch cooling crystallization with a temperature cycling method to produce a narrow crystal size distribution and grow a desired polymorphic form of sulfathiazole crystals. The study used focused beam reflectance measurement (FBRM), and attenuated total reflectance ultraviolet/visible (ATR-UV/vis)spectroscopy for the in situ monitoring and control of the process. Based on the FBRM readings, the process was driven using a feedback control approach that employs alternating cycles of heating and cooling phases so that the number of counts, corresponding to the number of seed particles, is maintained, whilst the square-weighted chord length distribution, indicating the dynamic progress of the growth of the seeds in the system, is increased. Results of the experiments show that the temperature cycling method promoted Ostwald ripening, which helped in accelerating the growth and enhancing the size uniformity of the product. The method also has a good prospect to be implemented for the control of polymorphic purity. Seeds of Form I and Form II could be grown from n-propanol and water, respectively. Form I seeds in water were first transformed into Form II and/or swamped by nuclei of Form II, before the growth of the newly formed crystals took place. Seeds of Form II and Form III in n-propanol, however, were not able to grow at all. This study confirmed that the nucleation and growth of sulfathiazole crystals are solvent-mediated, and the insight into these phenomena was captured very well by the in situ monitoring tools

Investigation of the effect of temperature cycling on surface features of sulfathiazole crystals during seeded batch cooling crystallization

The effect of temperature cycling on the surface features of sulfathiazole crystals was investigated using focused beam reflectance measurement (FBRM) and ex situ optical microscopy, scanning electron microscopy (SEM), and atomic forced microscopy (AFM). Smoothing of the crystal surface was observed during heating, while during cooling the smooth crystals showed features growing on their surfaces. These changes on the crystal surface were detected by the FBRM as an increase in the number of coarse counts during heating phases and a drop during cooling phases. Laser beam spreading caused by the surface changes and signal/chord splitting due to the formation of sharp edges are suggested as explanations for the FBRM results. The study shows the capability of FBRM to provide useful information with regard to the changes on the surface of the crystalline products, which could be linked to possible growth mechanisms. The information can be used to avoid problems in the downstream processing or in the final product property due to variations in flowability and friability, which are related to the crystal surface property

A combined approach of differential scanning calorimetry and hot-stage microscopy with image analysis in the investigation of sulfathiazole polymorphism

A combination of differential scanning calorimetry and hot-stage microscopy with image analysis has been used to investigate the polymorphism of sulfathiazole. The use of light intensity profiles obtained from the HSM images, as an alternative way to present results of the HSM analysis, was found to be useful in describing and verifying thermal events. The approach provides a unique insight into the polymorphic transformations and thermal behaviour exhibited by this compound. The results of the experiments show that sulfathiazole tends to crystallise as mixtures of polymorphs, even though the literature methods for producing pure polymorph were followed

Nanoparticle preparation of mefenamic acid by electrospray drying

Nanoparticles preparation of Mefenamic acid (MA) by using an electrospray drying method was conducted in this study. Electrospray drying is a process that uses electrostatic force to disperse a conductive liquid stream into fine charged droplets through the coulomb fission of charges in the liquid and finally dry into fine particles. Electrospray drying modes operation usually in Taylor cone jet, and it was formed by controlling applied voltage and liquid flow rate. A conductive liquid (2.77–8.55μScm−1) which is MA solution was prepared by using acetone with concentration 0.041 and 0.055 M before pumping at a flow rate of 3–6ml/h. By applying the applied voltage at 1.3–1.5 kV, Taylor cone jet mode was formed prior to the electrospray. During electrospray drying process, solvent evaporation from the droplet was occurring that leads to coulomb disruption and may generate to nanoparticles. The dried nanoparticles were collected on a grounded substrate that was placed at varying distance from the electrospray. MA particle with size range of 100–400 nm were produced by electrospray drying process. Characterization of particles by using X-ray diffractometry (XRD) and differential scanning calorimetry (DSC) show that particles formed into polymorph I

Prediction of mefenamic acid solubility and molecular interaction energies in different classes of organic solvents and water

Determination of solubility data either through experimental or model based approaches become a necessity in crystallization of pharmaceutical compound. The current work predicts the mefenamic acid solubility and molecular interaction energy, namely electrostatic (HMF), hydrogen bonding (H-HB) and van der Waals (H-vdW) in different solvents at temperatures from 298 to 323 K using Conductor-like Screening Model for Real Solvents (COSMO-RS). The solvents used were N, N-dimethylacetamide, N,N-dimethylformamide, acetone, ethyl acetate, ethanol, iso-propyl alcohol, n-hexane, n-heptane, cyclohexane and water. The Gibbs free energy of fusion required in COSMO-RS computation was determined using differential scanning calorimetry and reference solubility method. The accuracy of methods employed in prediction of solubility were evaluated using mean squared quadratic error (MSE). The mefenamic acid solubility predicted using COSMO-RS with reference solubility method showed a small MSE value, which was less than 2%. The predicted solubility also follows the same trend as the experimental values and increases with temperature. The predicted H-HB energy and Gibbs free energy changes of mefenamic acid dissolution in the solvents studied highly influence the solubility data. Therefore, COSMO-RS with reference solubility method is promising approach to predict solubility and intermolecular interaction energy of mefenamic acid in different solvents

Solubility and dissolution thermodynamic data of mefenamic acid crystals in different classes of Organic solvents

Different classes of solvents provide different polarity values, which influence the solubility of pharmaceutical solids. In this article, the solubility of mefenamic acid in different classes of organic solvents, including polar protic, dipolar aprotic, and apolar aprotics at a range of temperatures from (298 to 323) K are reported. It has been found that mefenamic acid shows high solubility in dipolar aprotic solvents (N,N-dimethylacetamide, N,N-dimethylformamide, ethyl acetate, and propanone), moderate solubility in polar protic solvents (ethanol and propan-2-ol), and poor solubility in apolar aprotic solvents (hexane, heptane, and cyclohexane) and water

The impact of direct nucleation control on crystal size distribution in pharmaceutical crystallization processes

The control of crystal size distribution (CSD) in pharmaceutical crystallization is of primary importance, as downstream processes such as filtration or drying are greatly affected by the properties of the CSD. It is recognized that the variability in the final CSD is mainly caused by the significant uncertainties in the nucleation rates, and therefore, a good control of nucleation events is necessary to achieve the desired CSD. In this paper, a new direct nucleation control (DNC) approach is introduced that directly controls the apparent onset of nucleation defined as the formation of new particles with detectable size using in situ instruments. The approach uses information on nucleation and dissolution, provided by focused beam reflectance measurement (FBRM), in a feedback control strategy that adapts the process variables, so that the desired quality of product is achieved, for example large crystals with a narrow CSD. In addition, DNC provides in situ fines removal through the operating protocol, rather than having additional equipment and external recycle loops. DNC does not require concentration measurement and has the advantage of being a model-free approach, requiring no information on nucleation or growth kinetics in order to design an operating curve. The DNC approach automatically and adaptively detects the boundary of the operating zone; hence it is more robust to the presence of impurities or residual solvent than the supersaturation control approach. The approach has been applied for the crystallization of glycine and experimental results demonstrate the benefits of DNC of producing larger crystals with narrower CSD compared to classical operations