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We have employed a bespoke setup combining confocal Raman microscopy and an ultraviolet–visible (UV–Vis) spectroscopy flow cell to investigate the effect of excipients on the disproportionation kinetics of Pioglitazone HCl (PioHCl) in tablets during dissolution. Three binary formulations of PioHCl, containing citric acid monohydrate (CA), lactose monohydrate (LM), or magnesium stearate (MgSt), respectively, were used as models to study the influence of excipients’ physicochemical properties on the rate of salt disproportionation kinetics and dissolution performance in different aqueous pH environments. It was found that formulation excipients can induce or prevent salt disproportionation by modulating the microenvironmental pH regardless of the pH of the dissolution media. Incorporating CA in PioHCl tablets preserves the salt form and enhances the dissolution performance of the salt in the acidic medium (pH = 1.2). In contrast, LM and MgSt had a detrimental effect on in vitro drug performance by inducing salt disproportionation in the tablet during dissolution in the same acidic medium. Dissolution in the neutral medium (pH = 6.8) showed rapid formation of the free base upon contact with the dissolution medium. The Raman maps of the cross-sectioned tablets revealed the formation of a shell consisting of the free base around the edge of the tablet. This shell decreased the rate of penetration of the dissolution medium into the tablet, which had significant implications on the release of the API into the surrounding solution, as shown by the UV–vis absorption spectroscopy drug release data. Our findings highlight the utility of the Raman/UV–vis flow cell analytical platform as an advanced analytical technique to investigate the effect of excipients and dissolution media on salt disproportionation in real time. This methodology will be used to enhance our understanding of salt stability studies that may pave the way for more stable multicomponent formulations.

In pharmaceutical preformulation it is important to be able to screen a drug compound for possible solid forms (amorphous, crystal, polymorphs, salts, etc.) prior to scale-up of manufacture for formulation, and as this screening is undertaken prior to scale-up, there is often only a small amount of drug material available. Minimizing the amount of sample required for these solid form investigations is therefore of paramount importance. Typical industrial work-flows require hundreds of milligrams of compound, while a small number of research papers have suggested that new approaches based on conventional inkjet printing may allow only a few milligrams to be used, but even these small quantities of the sample may not be available in early stage drug development. Herein we report an approach based on picoliter inkjet printing. Employing paracetamol as a model compound, we illustrate how a basic solid-form screen may be run using only nanograms of material (around 6 orders of magnitude less material than used in previously reported approaches). For the first time, we were able to monitor the recrystallization of nanogram amorphous paracetamol to metastable crystalline forms II and III. Cross-polarized microscopy and Raman spectroscopy were employed to monitor the recrystallization of the paracetamol microarray. We suggest that further development of this concept may allow preformulation to occur far earlier in drug development than is currently the case, and also a more extensive parameter space to be explored using this new approach in a microarray format.

A miniaturized, high-throughput assay was optimized to screen polymer–drug solid dispersions using a 2-D Inkjet printer. By simply printing nanoliter amounts of polymer and drug solutions onto an inert surface, drug/polymer microdots of tunable composition were produced in an easily addressable microarray format. The amount of material printed for each dried spot ranged from 25 ng to 650 ng. These arrays were used to assess the stability of drug/polymer dispersions with respect to recrystallization, using polarized light microscopy. One array with a panel of 6 drugs formulated at different ratios with a poly(vinylpyrrolidone-vinyl acetate) (PVPVA) copolymer was developed to estimate a possible bulk (gram-scale) approximation threshold from the final printed nanoamount of formulation. Another array was printed at a fixed final amount of material to establish a literature comparison of one drug formulated with different commercial polymers for validation. This new approach may offer significant efficiency in pharmaceutical formulation screening, with each experiment in the nanomicro-array format requiring from 3 up to 6 orders of magnitude lower amounts of sample than conventional screening methods.

Because of its weakly acidic nature (pKaof 4.5), indomethacin presents an aqueous solubility that significantly increases when changing from acidic to neutral/alkaline pH (1.5 μg/mL at pH 1.2 and 105.2 μg/mL at pH 7.4). We have therefore investigated the impact of the dissolution medium pH on the dissolution performance of indomethacin:Kollidon VA64 extrudates. The impact of the drug loading on the dissolution properties of these systems was also examined (5%, 15%, 30%, 50%, 70%, and 90% drug loading). Time-resolved Raman spectroscopy along with in-line UV–vis spectrophotometry was employed to directly relate changes in dissolution behavior to physicochemical changes that occur to the extrudate during the test. The dissolution tests were performed in pH 2 HCl (to mimic the stomach conditions), and this was then switched during the experiment to pH 6.8 phosphate buffer (to simulate the poststomach conditions). The rotating disc dissolution rate test was also used to simultaneously measure the dissolution rate of both the drug and the polymer. We found that in pH 2 HCl buffer, for the 15% or higher drug-loaded extrudates, Kollidon VA64 preferentially dissolves from the exterior of the compact leaving an amorphous drug-rich hydrophobic shell, which, similarly to an enteric coating, inhibits the drug release. The in situformation of an enteric coating has been previously hypothesized, and this has been the first time that is directly observed in a pH-variable dissolution test. The dissolution medium switch to pH 6.8 phosphate buffer, due to the large increase of the aqueous solubility of indomethacin at this pH, leads to rapid dissolution of the material forming the coating and therefore total drug release. In contrast, the 5% extrudate is fully hydrated and quickly dissolves at low pH pointing to a dissolution performance dependent on highly water-soluble Kollidon VA64.

Real-time in situRaman mapping has been employed to monitor, during dissolution, the crystallization transitions of amorphous bicalutamide formulated as a molecular dispersion in a copovidone VA64 matrix. The dissolution performance was also investigated using the rotating disc dissolution rate methodology, which allows simultaneous determination of the dissolution rate of both active ingredient and polymer. The dissolution behavior of two bicalutamide:copovidone VA64 dispersion formulations, containing 5% (w/w) and 50% (w/w) bicalutamide, respectively, was investigated, with the aim of exploring the effect of increasing the bicalutamide loading on the dissolution performance. Spatially time-resolved Raman maps generated using multivariate curve resolution indicated the simultaneous transformation of amorphous bicalutamide present in the 50% drug-loaded extrudate into metastable polymorphic form II and low-energy polymorphic form I. Fitting a kinetic model and spatially correlating the data extracted from the Raman maps also allowed us to understand the re-crystallization mechanisms by which the low-energy form I appears. Form I was shown to crystallize mainly directly from the amorphous solid dispersion, with crystallization from the metastable form II being a minor contribution.

In situ Raman spectroscopy and Raman mapping are used to monitor the crystallization of amorphous paracetamol in both covered and uncovered geometries, for which different crystallization pathways have been reported previously. The results suggest that surface crystallization predominates in the uncovered samples, leading to forms I and II, whereas in the covered samples bulk crystallization dominates and leads to form III.

We demonstrate for the first time the application of Principal Component Analysis (PCA) to the analysis of time-resolved energy-dispersive X-ray diffraction data. Previously well-characterised model systems are studied. PCA is shown to offer significant advantages over traditional curve-fitting methods in terms of speed and lack of potential user bias.

Manganocene, Cp2Mn, has been employed as a precursor in the synthesis of a range of Mnii dimers of the type CpMnμ-X2X 8-NHC9H6N 1, NPhC5H4N 2, N4-EtC6H4C5H4N 3 and CCPh 4 as well as the bis-adduct Cp2MnHNCNMe2225. The solid-state structures of 1–5are reported. Variable-temperature magnetic measurements have been used to assess the extent of Mnμ-XMn communication within the dimers of 1–4as a function of the bridging ligands X.

Manganocene, Cp₂Mn, has been employed as a precursor in the synthesis of a range of Mn(ii) dimers of the type [CpMn(μ-X)]₂ [X = 8-NHC₉H₆N (1), N(Ph)(C₅H₄N) (2), N(4-EtC₆H₄)(C₅H₄N) (3) and C&z.tbd;CPh (4)] as well as the bis-adduct [Cp₂Mn{HN&z.dbd;C(NMe₂)₂}₂] (5). The solid-state structures of 1–5 are reported. Variable-temperature magnetic measurements have been used to assess the extent of Mn(μ-X)Mn communication within the dimers of 1–4 as a function of the bridging ligands (X).

The reaction between pairs of enantiomeric cocrystals involving caffeine or theophylline and a chiral cocrystal former has been investigated by liquid-assisted grinding: we demonstrate two different outcomes for such cocrystal–cocrystal reactions.

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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.