Continuous cocrystallization of benzoic acid and isonicotinamide by mixing-induced supersaturation : exploring opportunities between reactive and antisolvent crystallization concepts

This study combines reactive and antisolvent crystallization concepts via mixing-induced supersaturation to demonstrate a wider range of options for solvent system selection in multicomponent crystallization. This approach was applied to investigate continuous crystallization of 1:1 and 2:1 cocrystals of benzoic acid and isonicotinamide. Design of Experiments was used to identify conditions where pure cocrystal phases are obtained and a continuous mixing-induced cocrystallization process was implemented to selectively produce either 1:1 or 2:1 cocrystals

Crystallization diagram for antisolvent crystallization of lactose : using design of experiments to investigate continuous mixing- induced supersaturation

This study investigates the effects of key process parameters of continuous mixing-induced supersaturation on the antisolvent crystallization of lactose using D-optimal Design of Experiments (DoE). Aqueous solutions of lactose were mixed isothermally with antisolvents using a concentric capillary mixer. Process parameters investigated were the choice of antisolvent (acetone or isopropanol), concentration of lactose solution, total mass flow rate, and the ratio of mass flow rates of lactose solution and antisolvent. Using a D-optimal DoE a statistically significant sample set was chosen to explore and quantify the effects of these parameters. The responses measured were the solid state of the lactose crystallized, induction time, solid yield and particle size. Mixtures of α-lactose monohydrate and β-lactose were crystallized under most conditions with β-lactose content increasing with increasing amount of antisolvent. Pure α-lactose monohydrate was crystallized using acetone as the antisolvent, with mass flow ratios near 1:1, and near saturated solutions of lactose. A higher resolution DoE was adopted for acetone and was processed using multivariate methods to obtain a crystallization diagram of lactose. The model was used to create an optimized process to produce α-lactose monohydrate and predicted results agreed well with those obtained experimentally, validating the model. The solid state of lactose, induction time, and solid yield were accurately predicted

Applying hyperspectral imaging to continuous processing of pharmaceuticals

Introduction and objectives: In moving from batch to continuous manufacturing of pharmaceutical products, knowledge of all experimental variables is required to help control and achieve a stable system that yields a consistent product with the desired attributes. Spectroscopic tools are often used to provide point measurements at key points in the process. Here we demonstrate the applicability of Hyperspectral Imaging (HSI) to continuous nuclaetion processes. The objective of the work described here was to show how HSI can be used to monitor mixing processes by providing spatially discriminated near-infrared spectra, yielding vital process information that has only previously been estimated using simulation techniques such as computational fluid dynamics (CFD). Methods: Water (antisolvent) and an IPA/water mixture (solvent) containing dissolved paracetamol seed crystals were mixed in a tube by introducing the antisolvent jet at different flow rates, and the resulting mixing in the tube was imaged with an InnoSpec RedEye camera in the spectral range 950 to 1700 nm. Microscope images of the resultant crystals from each different flow rate were taken to confirm that differences in the final crystal product were observed. Machine learning techniques in the form of Support Vector Machine (SVM) analysis were used to analyse and automatically separate the spectral data of the solvent/antisolvent mix into the different components. Results: The antisolvent jet, which resulted in nucleation near the point of injection, could clearly be identified and therefore monitored after application of the SVM. Differences between different flow rates and concentrations were observed from the hyperspectral images obtained, and these differences carried through to the shape and size of the final crystals obtained. Conclusions: We have demonstrated the applicability of HSI and advanced data processing techniques to the monitoring of mixing dynamics, in particular those used in continuous pharmaceutical processing such as solvent/antisolvent crystallisation

Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals

Quantitative Analysis of the Amorphous Phase and Multiple Polymorphs of Model Sulfa-Drugs; Sulfamerazine and Sulfathiazole

Polymorphic transformations are known to occur as a result of many factors, one of the most prominent being recrystallisation from different solutions. Though other factors have been known to induce polymorphic change, these can include environmental factors and mechanical/physical stress. During many manufacturing processes mechanical stress such as milling or compression can induce polymorphic transformation, as well as environmental effects during storage such as changes in temperature or humidity. In this body of work the solid state transformations of two model polymorphic drugs, sulfamerazine and sulfathiazole, were studied. For this accurate analytical methods were developed for comprehensive polymorphic analysis. Previous studies have shown the effects of mechanical stress on the solid state chemistry of sulfamerazine. It has already been shown that compression during tabletting can cause transformation from sulfamerazine form I (FI) to form II (FII), that cryo-milling can generate amorphous content, and milling at room temperature can transform FI to FII. In this work, methods to prepare bulk FII from FI were reviewed. Both forms I & II of sulfamerazine were monitored during milling at room temperature and low temperatures, achieving the first complete transformation to sulfamerazine\u27s amorphous phase (FA). FA produced from cryo-milling both FI and FII at different time intervals were compared to determine the optimal method to prepare (FA) for multivariate analysis. This optimal method resulted in the most stable amorphous phase, while taking the least amount of time to prepare. FI, FII and FA were used to prepare binary and ternary mixtures for chemometric models using XRPD, NIR and IR spectroscopy. This gave a novel means to analysis and monitors the solid state transformations of sulfamerazine observed during the room temperature milling and cryo-milling of FI and FII. The shelf-life of FA was also monitored when stored under vacuum at 4oC and room temperature using these calibration models. For the work with sulfathiazole, low content analysis of different solid sates was used to determine the limitations of a number of analytical techniques such as XRPD, NIR and IR spectroscopy. The analytical method that produced the most accurate calibrations was used in other studies. For the first time the amorphous phase of sulfathiazole was prepared via cryo-milling forms I and III. These produced purer samples of the amorphous phase when compared to samples prepared by the melt quench method. With a successful method to prepare pure samples of the amorphous phase, novel ternary studies containing the amorphous phase of sulfathiazole, and form I and form III were used to create ternary regression models from two different data sets, which were then compared. One ternary study was designed to focus on low content analysis, while the other was designed to focus on whole content analysis. The ternary system that gave the best results was then used to monitor the solid state transformations of forms I and III to the amorphous phase during cryo-milling

Investigation of the formation of drug-drug cocrystals and coamorphous systems of the antidiabetic drug gliclazide

The antidiabetic drug gliclazide (GLZ) has a slow absorption rate and a low bioavailability due to its poor solubility. GLZ is often prescribed along with an antihypertensive, as many diabetic patients have coexistent hypertension. Cocrystallization and coamorphization are attractive strategies to enhance dissolution rates and to reduce the number of medications a patient has to take. In this work the formation of cocrystals and coamorphous systems of GLZ with various antihypertensive drugs was studied, namely chlorothiazide (CTZ), hydrochlorothiazide (HTZ), indapamide (IND), triamterene (TRI) and nifedipine (NIF) as well as benzamidine (BZA) as a model for the amidine pharmacophore. TRI, IND and HTZ were found to form coamorphous systems with GLZ that are stable for at least six months at 22 +/- 2 degrees C and 56% relative humidity. Coamorphous GLZ-TRI is also stable in dissolution medium. Coamorphization of GLZ-TRI with 15% sodium taurocholate gave a viable coamorphous formulation with an enhanced dissolution rate. Comilling of GLZ with BZA and cocrystallization from solution gave the amorphous and crystalline salt, respectively and the X-ray structure is reported. During attempts to obtain X-ray suitable cocrystals crystals of Na(+)GLZ(+) and IND 0.5H(2)O were obtained. Redetermination of the published structure of IND 0.5H(2)O revealed a unit cell with the length of the a axis doubled, a different space group and no disorder. Liquid-assisted grinding of a 1:1 mixture of GLZ and IND indicated the transformation of IND to a new solid-state form, while GLZ remained unaltered. Milling- and heating-induced solid-state transformations of IND are discussed.This work was supported by Science Foundation Ireland under Grant No. [12/RC/2275] as part of the Synthesis and Solid State Pharmaceutical Centre (SSPC). M.A. acknowledges the Royal Embassy of Saudi Arabia for a Saudi Arabia Government Scholarship.peer-reviewed2020-02-2

The natural bile acid surfactant sodium taurocholate (NaTC) as a coformer in coamorphous systems: Enhanced physical stability and dissolution behavior of coamorphous drug-NaTc systems

The amorphization of 18 different drugs on milling with one mole equivalent sodium taurocholate (NaTC) was investigated. In all cases the X-ray powder pattern showed an amorphous halo after milling at room temperature or after cryomilling and 14 of the 18 coamorphous drug-NaTC systems were physically stable for between one to eleven months under ambient storage conditions. In three cases, namely carbamazepine-NaTC, indomethacin-NaTC and mefenamic acid-NaTC, significant dissolution advantages over the crystalline drugs were observed, both for the freshly prepared samples and after storage for seven months. To understand the increased physical stability, infrared-, near-infrared and Raman spectroscopic studies were carried out. The effectiveness of NaTC as a coformer in a diverse range of coamorphous systems is attributed to its awkward molecular shape that hampers recrystallization and phase separation and its propensity to form a range of similar, yet different drug-coformer hydrogen bonding arrangements.This work was supported by Science Foundation Ireland under Grant No. [12/RC/2275] as part of the Synthesis and Solid State Pharmaceutical Centre (SSPC).peer-reviewed2019-10-2

Investigation of the formation of drug-drug cocrystals and coamorphous systems of the antidiabetic drug gliclazide

The antidiabetic drug gliclazide (GLZ) has a slow absorption rate and a low bioavailability due to its poor solubility. GLZ is often prescribed along with an antihypertensive, as many diabetic patients have coexistent hypertension. Cocrystallization and coamorphization are attractive strategies to enhance dissolution rates and to reduce the number of medications a patient has to take. In this work the formation of cocrystals and coamorphous systems of GLZ with various antihypertensive drugs was studied, namely chlorothiazide (CTZ), hydrochlorothiazide (HTZ), indapamide (IND), triamterene (TRI) and nifedipine (NIF) as well as benzamidine (BZA) as a model for the amidine pharmacophore. TRI, IND and HTZ were found to form coamorphous systems with GLZ that are stable for at least six months at 22 +/- 2 degrees C and 56% relative humidity. Coamorphous GLZ-TRI is also stable in dissolution medium. Coamorphization of GLZ-TRI with 15% sodium taurocholate gave a viable coamorphous formulation with an enhanced dissolution rate. Comilling of GLZ with BZA and cocrystallization from solution gave the amorphous and crystalline salt, respectively and the X-ray structure is reported. During attempts to obtain X-ray suitable cocrystals crystals of Na(+)GLZ(+) and IND 0.5H(2)O were obtained. Redetermination of the published structure of IND 0.5H(2)O revealed a unit cell with the length of the a axis doubled, a different space group and no disorder. Liquid-assisted grinding of a 1:1 mixture of GLZ and IND indicated the transformation of IND to a new solid-state form, while GLZ remained unaltered. Milling- and heating-induced solid-state transformations of IND are discussed.This work was supported by Science Foundation Ireland under Grant No. [12/RC/2275] as part of the Synthesis and Solid State Pharmaceutical Centre (SSPC). M.A. acknowledges the Royal Embassy of Saudi Arabia for a Saudi Arabia Government Scholarship.2020-02-2

Effects of ball-milling and cryomilling on sulfamerazine polymorphs: A quantitative study

The effects of ball-milling and cryomilling on sulfamerazine forms I and II (SMZ FI, FII) were investigated using X-ray powder diffraction, infrared and near-infrared (NIR) spectroscopy. Cryomilling resulted in a complete amorphization of both polymorphs. Milling at room temperature gave mixtures of amorphous SMZ (FA) and FII. Calibration models were developed for the quantitative analysis of binary (FI/FII, FI/FA, and FII/FA) and ternary (FI/FII/FA) mixtures using NIR spectroscopy combined with partial least-squares (PLS) regression. The PLS models for binary (0%-100%), ternary (0%-100%), and low-level (0%-10%) binary mixtures had root-mean-square errors of prediction of 1.8%, 5.1%, and 0.80%, respectively. The calibration models were used to obtain a detailed quantitative picture of solid-state transformations during milling and any subsequent recrystallizations. FA prepared by cryomilling FI for less than 60 min recrystallized to mixtures of FI and FII, whereas samples milled for more than 60 min crystallized to pure FII. The effect of comilling SMZ with stoichiometric amounts of additives was investigated. SMZ formed amorphous materials with oxalic, dl-tartaric, and citric acids that were more stable toward recrystallization than FA. Amorphous SMZ/oxalic acid was found to recrystallize to a 2:1 cocrystal during storage. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm SciThis work was supported by Science Foundation Ireland under Grant No. [07/SRC/B1158] as part of the Solid State Pharmaceutical Cluster (SSPC). Mr. Dermot McGrath is thanked for DSC measurements

Continuous crystallisation of organic salt polymorphs

Organic salt crystallisation is of great importance to the pharmaceutical industry as many pharmaceutical products are marketed as salts with salt formation being an essential step in drug development. The model compound used in this work is the polymorphic organic salt ethylenediammonium 3,5-dinitrobenzoate (EDNB) which is the 2:1 salt of 3,5-dinitrobenzoic acid with ethylenediamine. Crystallisation of the two EDNB polymorphs, the stable monoclinic form and the metastable triclinic form, was performed in both semi-batch and continuous processes using continuous mixing approaches. It was demonstrated that continuous mixing approaches, using various types of continuous mixers (co-axial, Ehrfeld, X-mixer) can be used to crystallise the EDNB salt with consistent yield and particle size distribution while achieving control over polymorphic form. The experiments were designed with use of a solution speciation model which provided process understanding and insight to guide development of salt crystallisation processes