Dhara Raijada

Raman spectroscopy in pharmaceutical product design

Almost 100 years after the discovery of the Raman scattering phenomenon, related analytical techniques have emerged as important tools in biomedical sciences. Raman spectroscopy and microscopy are frontier, non-invasive analytical techniques amenable for diverse biomedical areas, ranging from molecular-based drug discovery, design of innovative drug delivery systems and quality control of finished products. This review presents concise accounts of various conventional and emerging Raman instrumentations including associated hyphenated tools of pharmaceutical interest. Moreover, relevant application cases of Raman spectroscopy in early and late phase pharmaceutical development, process analysis and micro-structural analysis of drug delivery systems are introduced. Finally, potential areas of future advancement and application of Raman spectroscopic techniques are discussed.

A Step Toward Development of Printable Dosage Forms for Poorly Soluble Drugs

The purpose of this study was to formulate printable dosage forms for a poorly soluble drug (piroxicam; PRX) and to gain understanding of critical parameters to be considered during development of such dosage forms. Liquid formulations of PRX were printed on edible paper using piezoelectric inkjet printing (PIJ) and impression printing (flexography). The printed dosage forms were characterized using scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) and the amount of drug was determined using high-performance liquid chromatography. Solutions of PRX in polyethylene glycol 400 (PEG-400):ethanol (40:60) and in PEG-400 were found to be optimal formulations for PIJ and flexography, respectively. SEM-EDX analysis revealed no visible solid particles on the printed dosage forms indicating the drug most likely remained in solution after printing. More accurate drug deposition was obtained by PIJ as compared with flexography. More than 90% drug release was achieved within 5 min regardless of printing method used. The solubility of drug in solvents/cosolvents, rheological properties of formulations, properties of substrate, feasibility and accuracy of the printing methods, and detection limit of analytical techniques for characterization of printed dosage forms are some of the concerns that need to be addressed for development of printable dosage forms of poorly soluble drugs.

Exploring the solid-form landscape of pharmaceutical hydrates: transformation pathways of the sodium naproxen anhydrate-hydrate system.

ABSTRACTPurposeTo understand the transformation pathways amongst anhydrate/hydrate solid forms of sodium naproxen and to highlight the importance of a polymorphic dihydrate within this context.MethodsMulti-temperature dynamic vapour sorption (DVS) analysis combined with variable-humidity X-ray powder diffraction (XRPD) to establish the transformation pathways as a function of temperature and humidity. XRPD and thermogravimetric analysis (TGA) to characterise bulk samples. Monitoring of in-situ dehydration using solid-state 13C CP/MAS spectroscopy.ResultsAt 25°C, anhydrous sodium naproxen (AH) transforms directly to one dihydrate polymorph (DH-II). At 50°C, AH transforms stepwise to a monohydrate (MH) then to the other dihydrate polymorph (DH-I). DH-II transforms to a tetrahydrate (TH) more readily than DH-I transforms to TH. Both dihydrate polymorphs transform to the same MH.ConclusionsThe properties of the polymorphic dihydrate control the transformation pathways of sodium naproxen.

Characterization of degradation products of amorphous and polymorphic forms of clopidogrel bisulphate under solid state stress conditions.

The present study deals with the stress degradation studies on amorphous and polymorphic forms of clopidogrel bisulphate. The objective was to characterize the degradation products and postulate mechanism of decomposition of the drug under solid state stress conditions. For that, amorphous form, polymorph I and polymorph II of the drug were exposed to 40 degrees C/75% relative humidity (RH), with and without stressors for 3 months. The samples were analyzed by HPLC, and the relative extent of degradation as well as nature of decomposition was compared among three solid forms. In total, eight degradation products were observed under various stress conditions. The structures of all of them were elucidated using LC-MS/TOF and LC-MS(n) studies. While one matched the known hydrolytic decomposition product of the drug in solution, seven others were new. The postulated degradation pathway and mechanism of decomposition are discussed.

A high throughput platform for understanding the influence of excipients on physical and chemical stability

The present study puts forward a miniaturized high-throughput platform to understand influence of excipient selection and processing on the stability of a given drug compound. Four model drugs (sodium naproxen, theophylline, amlodipine besylate and nitrofurantoin) and ten different excipients were selected. Binary physical mixtures of drug and excipient were transferred to a 96-well plate followed by addition of water to simulate aqueous granulation environment. The plate was subjected for XRPD measurements followed by drying and subsequent XRPD and HPLC measurements of the dried samples. Excipients with different water sorbing potential were found to influence distinctly on the phase transformation behaviour of each drug. Moreover, the amount of water addition was also a critical factor affecting phase transformation behaviour. HPLC analysis revealed one of the drug:excipient pairs with a tendency for chemical degradation. The proposed high-throughput platform can be used during early drug development to simulate typical processing induced stress in a small scale and to understand possible phase transformation behaviour and influence of excipients on this.

Structural basis for the transformation pathways of the sodium naproxen anhydrate-hydrate system

Relationships between the crystal structures of two polymorphs of sodium naproxen dihydrate and its monohydrate and anhydrate phases provide a basis to rationalize the observed transformation pathways in the sodium (S)-naproxen anhydrate–hydrate system.

Properties of the Sodium Naproxen-Lactose-Tetrahydrate Co-Crystal upon Processing and Storage

Co-crystals and co-amorphous systems are two strategies to improve the physical properties of an active pharmaceutical ingredient and, thus, have recently gained considerable interest both in academia and the pharmaceutical industry. In this study, the behavior of the recently identified sodium naproxen-lactose-tetrahydrate co-crystal and the co-amorphous mixture of sodium, naproxen, and lactose was investigated. The structure of the co-crystal is described using single-crystal X-ray diffraction. The structural analysis revealed a monoclinic lattice, space group P21, with the asymmetric unit containing one molecule of lactose, one of naproxen, sodium, and four water molecules. Upon heating, it was observed that the co-crystal transforms into a co-amorphous system due to the loss of its crystalline bound water. Dehydration and co-amorphization were studied using synchrotron X-ray radiation and thermogravimetric analysis (TGA). Subsequently, different processing techniques (ball milling, spray drying, and dehydration) were used to prepare the co-amorphous mixture of sodium, naproxen, and lactose. X-ray powder diffraction (XRPD) revealed the amorphous nature of the mixtures after preparation. Differential scanning calorimetry (DSC) analysis showed that the blends were single-phase co-amorphous systems as indicated by a single glass transition temperature. The samples were subsequently tested for physical stability under dry (silica gel at 25 and 40 °C) and humid conditions (25 °C/75% RH). The co-amorphous samples stored at 25 °C/75% RH quickly recrystallized into the co-crystalline state. On the other hand, the samples stored under dry conditions remained physically stable after five months of storage, except the ball milled sample stored at 40 °C which showed signs of recrystallization. Under these dry conditions, however, the ball-milled co-amorphous blend crystallized into the individual crystalline components.

Anhydrate to hydrate solid-state transformations of carbamazepine and nitrofurantoin in biorelevant media studied in situ using time-resolved synchrotron X-ray diffraction

Transformation of the solid-state form of a drug compound in the lumen of the gastrointestinal tract may alter the drug bioavailability and in extreme cases result in patient fatalities. The solution-mediated anhydrate-to-hydrate phase transformation was examined using an in vitro model with different biorelevant media, simulated fasted and fed state intestinal fluids containing bile salt and dioleoylphosphatidylcholine (DOPC) micelles, DOPC/sodium dodecyl sulfate (SDS) mixture, bile salt solution and water. Two anhydrate compounds (carbamazepine, CBZ and nitrofurantoin, NF) with different overall transformation time into hydrate form were used as model compounds. The transformations were monitored using direct structural information from time-resolved synchrotron X-ray diffraction. The kinetics of these transformations were estimated using multivariate data analysis (principal component analysis, PCA) and compared to those for nitrofurantoin (NF). The study showed that the solution-mediated phase transformation of CBZ anhydrate was remarkably faster in the DOPC/SDS medium compared to transformation in all the other aqueous dispersion media. The conversion time for CBZ anhydrate in water was shorter than for DOPC/SDS but still faster than the conversion seen in fed and fasted state micellar media. The conversion of CBZ anhydrate to hydrate was the slowest in the solution containing bile salt alone. In contrast, the solution-mediated phase transformations of NF did only show limited kinetic dependence on the dispersion media used, indicating the complexity of the nucleation process. Furthermore, when the CBZ and NF material was compacted into tablets the transformation times were remarkably slower. Results suggest that variations in the composition of the contents of the stomach/gut may affect the recrystallization kinetics, especially when investigating compounds with relatively fast overall transformation time, such as CBZ.

Near-infrared chemical imaging (NIR-CI) of 3D printed pharmaceuticals.

Hot-melt extrusion and 3D printing are enabling manufacturing approaches for patient-centred medicinal products. Hot-melt extrusion is a flexible and continuously operating technique which is a crucial part of a typical processing cycle of printed medicines. In this work we use hot-melt extrusion for manufacturing of medicinal films containing indomethacin (IND) and polycaprolactone (PCL), extruded strands with nitrofurantoin monohydrate (NFMH) and poly (ethylene oxide) (PEO), and feedstocks for 3D printed dosage forms with nitrofurantoin anhydrate (NFAH), hydroxyapatite (HA) and poly (lactic acid) (PLA). These feedstocks were printed into a prototype solid dosage form using a desktop 3D printer. These model formulations were characterized using near-infrared chemical imaging (NIR-CI) and, more specifically, the image analytical data were analysed using multivariate curve resolution-alternating least squares (MCR-ALS). The MCR-ALS algorithm predicted the spatial distribution of IND and PCL in the films with reasonable accuracy. In the extruded strands both the chemical mapping of the components in the formulation as well as the solid form of the active compound could be visualized. Based on the image information the total nitrofurantoin and PEO contents could be estimated., The dehydration of NFMH to NFAH, a process-induced solid form change, could be visualized as well. It was observed that the level of dehydration increased with increasing processing time (recirculation during the mixing phase of molten PEO and nitrofurantoin). Similar results were achieved in the 3D printed solid dosage forms produced from the extruded feedstocks. The results presented in this work clearly demonstrate that NIR-CI in combination with MCR-ALS can be used for chemical mapping of both active compound and excipients, as well as for visualization of solid form variation in the final product. The suggested NIR-CI approach is a promising process control tool for characterization of innovative patient-centred medicinal products.

Miniaturized Approach for Excipient Selection During the Development of Oral Solid Dosage Form

The present study introduces a miniaturized high-throughput platform to understand the influence of excipients on the performance of oral solid dosage forms during early drug development. Wet massing of binary mixtures of the model drug (sodium naproxen) and representative excipients was followed by sieving, drying, and compaction of the agglomerated material. The mini-compacts were subjected to stability studies at 25°C/5% relative humidity (RH), 25°C/60% RH and 40°C/75% RH for 3 months. The physical stability of the drug was affected by the storage condition and by the characteristics of the excipients, whereas all the samples were chemically stable. Force-distance curves obtained during the compression of agglomerated material were used for the comparison of compressibility of different drug-excipient mixtures. The agglomerated drug-excipient mixtures were also subjected to studies of the dissolution trend under sequential pH conditions to simulate pH environment of gastrointestinal tract. Major factors affecting the dissolution behavior were the diffusion layer pH of the binary mixtures and the ability of the excipients to alter the diffusion layer thickness. The proposed approach can be used for excipient selection and for early-stage performance testing of active pharmaceutical ingredient intended for oral solid dosage form.