Denise M. Croker

A comparative study of the use of powder X-ray diffraction, Raman and near infrared spectroscopy for quantification of binary polymorphic mixtures of piracetam

Diffraction and spectroscopic methods were evaluated for quantitative analysis of binary powder mixtures of FII(6.403) and FIII(6.525) piracetam. The two polymorphs of piracetam could be distinguished using powder X-ray diffraction (PXRD), Raman and near-infrared (NIR) spectroscopy. The results demonstrated that Raman and NIR spectroscopy are most suitable for quantitative analysis of this polymorphic mixture. When the spectra are treated with the combination of multiplicative scatter correction (MSC) and second derivative data pretreatments, the partial least squared (PLS) regression model gave a root mean square error of calibration (RMSEC) of 0.94 and 0.99%, respectively. FIII(6.525) demonstrated some preferred orientation in PXRD analysis, making PXRD the least preferred method of quantification.

Epitaxial growth of polymorphic systems: The case of sulfathiazole

The creation of composite crystals formed by the epitaxial interaction between differing polymorphs of sulfathiazole (forms II and IV) has been reported through the experimental growth from ethanol. The intermolecular interaction between the crystal phases was calculated by application of the differential evolution global optimisation algorithm. This indicates that the interaction between form IV and form II is greater than that between form IV and itself, but less than that between form II and itself. Thus from the initial nucleation of form IV the creation of form II through mismatching of the growth units would be favoured leading the growth of form II. This mechanism explains the structure of the observed crystals with an inner layer of form IV surrounded by a shell of form II.

Analysis of FII crystals of sulfathiazole: epitaxial growth of FII on FIV

This work describes the phenomenon of a less stable polymorph wedged as a middle layer in a more stable polymorph of sulfathiazole. Isolation of the pure FII polymorph of sulfathiazole consistently yielded crystals with a distinctive middle layer. Raman spectroscopy and X-ray diffraction have identified this middle layer as another polymorph of sulfathiazole, namely FIV. The solubilities of FII and FIV sulfathiazole are almost identical, with FIV slightly more soluble. It is thought that this causes FIV to nucleate first, followed by the epitaxial growth of FII. A morphological examination of the crystals demonstrated that the (100) face of the FII crystal matches the (10) face of the FIV crystal. It is proposed that the similarity of these faces supports the epitaxial growth of the FII polymorph on the surface of the FIV polymorph.

Low temperature fused deposition modeling (FDM) 3D printing of thermolabile drugs

ABSTRACT Fused deposition modelling (FDM) is the most commonly investigated 3D printing technology for the manufacture of personalized medicines, however, the high temperatures used in the process limit its wider application. The objective of this study was to print low‐melting and thermolabile drugs by reducing the FDM printing temperature. Two immediate release polymers, Kollidon VA64 and Kollidon 12PF were investigated as potential candidates for low‐temperature FDM printing. Ramipril was used as the model low melting temperature drug (109°C); to the authors’ knowledge this is the lowest melting point drug investigated to date by FDM printing. Filaments loaded with 3% drug were obtained by hot melt extrusion at 70°C and ramipril printlets with a dose equivalent of 8.8mg were printed at 90°C. HPLC analysis confirmed that the drug was stable with no signs of degradation and dissolution studies revealed that drug release from the printlets reached 100% within 20–30min. Variable temperature Raman and solid state nuclear magnetic resonance (SSNMR) spectroscopy techniques were used to evaluate drug stability over the processing temperature range. These data indicated that ramipril did not undergo degradation below its melting point (which is above the processing temperature range: 70–90°C) but it was transformed into the impurity diketopiperazine upon exposure to temperatures higher than its melting point. The use of the excipients Kollidon VA64 and Kollidon 12PF in FDM was further validated by printing with the drug 4‐aminosalicylic acid (4‐ASA), which in previous work was reported to undergo degradation in FDM printing, but here it was found to be stable. This work demonstrates that the selection and use of new excipients can overcome one of the major disadvantages in FDM printing, drug degradation due to thermal heating, making this technology suitable for drugs with lower melting temperatures.

Crystal nucleation of salicylic acid in organic solvents

The crystal nucleation of salicylic acid was explored in a range of solvents using induction time and metastable zone width measurements. In total 3100 experiments were performed to collect statistically valid nucleation results. The lognormal cumulative probability function provided a representative fit for both induction time and metastable zone width distributions. At equal driving force the induction time is found to increase in the order chloroform, ethyl acetate, acetonitrile, acetone, methanol and acetic acid, and this order agrees with the order of increasing interfacial energy The metastable zone width (MSZW) value (expressed as supersaturation driving force) was highest in acetic acid followed by a lower value in methanol, consistent with the induction time results. In ethyl acetate, acetonitrile and acetone the corresponding MSZW values were lower but the order among these three solvents varied depending on the cooling rate and saturation temperature. A novel format for comparing the induction time and MSZW experiments is presented. The analysis reveals that the time of nucleation in the metastable zone width experiments is also dependent on the time of transforming clusters into nuclei, and not only governed by the rate of supersaturation generation. The relative influence of this transformation time depends on the solvent and the cooling rate.

Solution mediated phase transformations between co-crystals

A solution mediated transformation between two co-crystal phases has been observed for the p-toluensulfonamide–triphenylphosphine oxide co-crystal system. This system has two known co-crystals with 1 : 1 and 3 : 2 stoichiometry respectively, and the ternary phase diagram (TPD) for the system has been determined in acetonitrile previously. By manipulating the solution composition in this solvent to a region of the TPD where the 1 : 1 co-crystal is stable, the 3 : 2 co-crystal could be observed to convert to the 1 : 1 co-crystal. The corresponding transformation was true for the 1 : 1 co-crystal in a region of the TPD where the 3 : 2 co-crystal is stable; the 1 : 1 co-crystal converted to the 3 : 2 co-crystal.

Artificial neural network modelling of continuous wet granulation using a twin-screw extruder

Computational modelling of twin-screw granulation was conducted by using an artificial neural network (ANN) approach. Various ANN configurations were considered with changing hidden layers, nodes and activation functions to determine the optimum model for the prediction of the process. The neural networks were trained using experimental data obtained for granulation of pure microcrystalline cellulose using a 12mm twin-screw extruder. The experimental data were obtained for various liquid binder (water) to solid ratios, screw speeds, material throughputs, and screw configurations. The granulate particle size distribution, represented by d-values (d10, d50, d90) were considered the response in the experiments and the ANN model. Linear and non-linear activation functions were taken into account in the simulations and more accurate results were obtained for non-linear function in terms of prediction. Moreover, 2 hidden layers with 2 nodes per layer and 3-Fold cross-validation method gave the most accurate simulation. The results revealed that the developed ANN model is capable of predicting granule size distribution in high-shear twin-screw granulation with a high accuracy in different conditions, and can be used for implementation of model predictive control in continuous pharmaceutical manufacturing.

Inkjet printing of paracetamol and indomethacin using electromagnetic technology: Rheological compatibility and polymorphic selectivity

Abstract Drop‐on‐demand inkjet printing is a potential enabling technology both for continuous manufacturing of pharmaceuticals and for personalized medicine, but its use is often restricted to low‐viscosity solutions and nano‐suspensions. In the present study, a robust electromagnetic (valvejet) inkjet technology has been successfully applied to deposit prototype dosage forms from solutions with a wide range of viscosities, and from suspensions with particle sizes exceeding 2 &mgr;m. A detailed solid‐state study of paracetamol, printed from a solution ink on hydroxypropyl methylcellulose (HPMC), revealed that the morphology of the substrate and its chemical interactions can have a considerable influence on polymorphic selectivity. Paracetamol ink crystallized exclusively into form II when printed on a smooth polyethylene terephthalate substrate, and exclusively into form I when in sufficient proximity to the rough surface of the HPMC substrate to be influenced by confinement in pores and chemical interactions. The relative standard deviation in the strength of the dosage forms was <4% in all cases, for doses as low as 0.8 mg, demonstrating the accuracy and reproducibility associated with electromagnetic inkjet technology. Good adhesion of indomethacin on HPMC was achieved using a suspension ink with hydroxypropyl cellulose, but not on an alternative polyethylene terephthalate substrate, emphasising the need to tailor the binder to the substrate. Future work will focus on lower‐dose drugs, for which dosing flexibility and fixed dose combinations are of particular interest. Graphical abstract Figure. No caption available.

Investigating the dissolution of the metastable triclinic polymorph of carbamazepine using in situ microscopy

Despite a tendency to undergo solution-mediated polymorphic transformation, the dissolution behaviour of the metastable FI (triclinic) polymorph of the pharmaceutical compound carbamazepine (CBZ) was investigated using in situ optical microscopy. Experiments were performed at an undersaturation where single crystals of the metastable FI polymorph dissolved. Dissolution in different solvents was investigated at a constant undersaturation. Separately the sublimation of FI was examined and additionally the dissolution was observed at undersaturations where the more stable FIII polymorph crystallized. The results show that both the dissolution and sublimation of FI occur primarily in the direction of the a-axis of the FI crystal structure where the CBZ molecules are found to stack in this direction. The order for the dissolution rate of FI was acetonitrile ≥ methanol > ethanol. The order of the dissolution rates in each of the solvents is inversely correlated to the viscosity and the binding energy of the solvents with the (100) surface of FI in each of the solvents. This suggests that the rate determining step for the dissolution may be either the diffusion or the detachment of CBZ molecules from the surface of FI. A notable difference in dissolution behaviour is also observed at undersaturations where the more stable FIII polymorph nucleates and grows.

Predicting optimal wet granulation parameters for extrusion-spheronisation of pharmaceutical pellets using a mixer torque rheometer

Mixer torque rheometry (MTR) was evaluated as a pre-production (pre-formulation and optimization) tool for predicting ideal liquid-to-solid ratios (L/S) for extrusion-spheronisation of a wide range of APIs using 10g formulations. APIs of low, medium and high solubility were formulated at low and high loadings (15 and 40% w/w, respectively) with PVP as binder (5%) and MCC as the major excipient. L/S corresponding to the maximum torque produced during wet massing in the MTR, L/S(maxT), was 0.8 for the low solubility APIs, which decreased to 0.6 for some of the more soluble APIs, especially at high loadings. Formulations extruded-spheronised at L/SmaxT) produced pellets of acceptable size (between 900 and 1400um) for all formulations, but mostly of unacceptable shape (dumb-bells of aspect ratio 1.2). Increasing L/S by 25% successfully produced spherical or near-spherical (aspect ratio 1.1) pellets for all formulations except one of the highly soluble APIs (piracetam) at high loading. Overall, MTR was demonstrated to be a useful pre-formulation and optimization tool in extrusion-spheronisation.