Particle size reduction technologies aiming to obtain amorphous nanoparticulate systems have gained a lot of attention. Co-milling of active pharmaceutical ingredient (API) with polymers is an attractive approach for pharmaceutical industry to prepare and stabilise the amorphous state. In this study, piroxicam anhydrate form I (PRXAH I) was used as a model API and PVP25, PVP90, and Soluplus® as model polymers. Co-milling was performed both at room and low temperature. The physical stability of the obtained samples was analysed using variable temperature X-ray powder diffractometry (VT-XRPD), DSC, Raman, and FT-NIR, and further, the dissolution performance was tested in the presence of simulated gastric fluid with both at-line XRPD and on-line Raman spectroscopy. Multivariate data analyses were applied to further visualise the data. Co-milling with polymers, PVP25 and PVP90, was sufficient to produce amorphous PRX system already at room temperature. Stability of these co-milled samples was dependent on the PRXAH I–polymer ratio. Dissolution of amorphous PRX from co-milled solid dispersions was compared with the physical mixtures with the same polymers. Recrystallisation of amorphous PRX was observed in the presence of simulated gastric fluid and it was already observed within the first three minutes of testing. Both methods (XRPD and Raman) revealed that amorphous PRX crystallised as PRX monohydrate during dissolution testing. Co-milling can be considered as a suitable method for preparation of stable mixtures of amorphous PRX and polymers. Further insight into the dissolution behaviour of prepared samples was obtained with both XRPD and Raman.

Purpose: In this work a UV imaging method was used to characterize the dissolution behavior of amlodipine besilate solid state forms. Methods: Monohydrate (MH) and dihydrate (DH) forms of amlodipine besilate (AMB) were prepared by recrystallization of anhydrate AMB in water. The amorphous AMB form (AM) was prepared by dehydration of the MH. The samples were compacted by weighing of 6 mg of substance into a steel cylinder (Ø: 2 mm). A torque screwdriver was used to obtain the same compression force for all samples. UV imaging of a dissolution cell (560 μl volume; 3 mm light path) was performed at 280 nm in an area of 9x7 mm. Light microscopy and Raman spectroscopy were utilized before and after UV imaging for solid form identification. Results: The UV imaging technique facilitated the acquisition of spatially and temporarily resolved intrinsic dissolution data of AMB. The AM had a higher dissolution rate than the DH sample. However, Raman spectroscopy showed that the thermodynamically metastable AM sample converted into the monohydrate upon contact with the dissolution media. The high dissolution rate of the AM samples may thus be influenced by an increase in surface area stemming from recrystallization on the compact surface, as well as a higher intrinsic dissolution of the amorphous and MH form. The increase in surface area was showed from both light microscopy and UV imaging. The Raman data displayed that the DH samples did not convert during dissolution. Conclusion: The highly spatially and temporarily resolved data enabled byUV imaging showed a difference between the dissolution rate of AM and DH samples. UV images indicated that AM samples recrystallized during the dissolution experiment, which was verified by Raman. The dissolution rate of the AM samples may have been influenced by the increased surface area generated by this recrystallization.

Solid state properties of pharmaceutical materials can influence their physical and chemical stability and other performance characteristics of the final product. Spray drying generally produces particles with a given size distribution, which can be subjected to solid state changes during spray drying operation. Solid state can be affected by the process conditions (i.e. fast or slow evaporation rate) inside the spray dryer. The aim of this study was to investigate the polymorphic variation of spray dried mannitol as a function of particle size. A spray dried system with a mixed mannitol polymorphs was produced by using 10% ethanol solution. The obtained dry powders were then dispensed into different size fractions using a Next Generation Pharmaceutical Impactor (NGI). The morphology and polymorphic form of mannitol were analyzed using SEM and XRPD and Raman Microscopy, respectively. Chemometrics was also applied to interpret the Raman spectra. A PLS-DA model with 3 principal components was built to describe the variation of Raman spectra and distinguish different solid state species. XRPD studies indicated that α- and β-mannitol were present in the 10% ethanol spray dried system. Further investigations with Raman studies revealed that more α-mannitol was present in smaller particles, suggesting that the presence of ethanol may affect the evaporation rate in smaller droplets, and by this means crystal arrangement of mannitol. Image analysis from the SEM figures showed a variation of size distribution between NGI stages. In conclusion, the polymorphic forms of spray-dried mannitol could change as a function of particle size. This finding provides guidance to improve dry powder formulations, especially for inhalation purposes, as produced by spray drying, since particle size is a critical component for therapeutic delivery.

Objective: To improve the efficiency of aerosolisation in an air flow of two model micronized drug powders by dry mechanical modification of particle surfaces. Method: Two model drugs, micronized salbutamol sulphate (SS) and salmeterol xinaofoate (SX) powders were dry coated with magnesium stearate using a mechanofusion approach. The powder resuspension and de-agglomeration behaviours were evaluated from a simple inhaler device actuated with a standard airflow, using a real-time particle sizer (Spraytec) to assess the aerosols generated. The work was further supported by examining aerodynamic behaviour using an in vitro twin stage impinger. Results and Discussion: The Spraytec results indicated that a substantial improvement in de-agglomeration efficiency during the aerosolization could be achieved for micronized drug particles, with a decrease of D₅₀ from 8.1 µm to 5.0 µm for SS and from 7.7 µm to 4.5 µm for SX, after the mechanofusion processing. The fine particle fraction values from the in vitro assessment were also increased significantly from 51% to 69% for SS and from 59.9% to 73.1% for SX. Conclusions: This study is part of a programme to better understand the flow and aerosolisation changes afforded by dry coating of a range of materials, and indicated that the aerosolisation performance of carrier-free powder formulations can be substantially improved by reducing the intrinsic cohesion of the powder via appropriate particle surface modification.

The spectroscopic techniques (viz. Near Infrared Spectroscopy, Raman Spectroscopy etc.) are widely used as Process Analytical Technology (PAT) tools supporting the Quality by Design (QbD) Concept. Furthermore, advancements in multivariate data analysis approaches have enabled extraction of information from complex dataset. The present study focuses on evaluating the feasibility of NIR spectroscopy as a PAT tool to understand phase transformations of anhydrate and hydrate forms of naproxen sodium (NS) during pharmaceutical development. NS is known to exist in anhydrate, various hydrate and solvate forms^1,2,3. In the present study, four solid forms of NS i.e. anhydrate, monohydrate, dihydrate and tetrahydrate forms were used. The monohydrate form was generated by recrystallization from 64 mol% methanol. The dihydrate and tetrahydrate forms were generated by exposing the anhydrate form at higher relative humidity conditions. The generated solid forms were confirmed by PXRD (Powder X-Ray Diffraction). The NIR spectra were evaluated using multivariate data analysis (Principle Component Analysis (PCA)). The identity and phase purity of the solid forms were confirmed by PXRD measurements. The NIR spectra were also distinct among the four solid forms. Scores plot of PCA depicted good separation among the four solid forms. The loadings plots (PC1 and PC2) indicated that the C-H and O-H spectral regions were most contributing to the separation observed in the scores plot. Thus, the present study indicates the feasibility of NIR spectroscopy to efficiently monitor phase transformation of NS. Future studies will focus on development of NIR based quantitative model that can be applied for online monitoring of hydrate formation and dehydration behaviour of the NS solid forms during processing and storage. References: 1. Krystle J. Chavez et. al., Crystal Growth & Design, Vol. 10, 2010, 3372-77 2. Piera Di Martino et. al., Journal of Pharmaceutical Sciences, Vol. 96, 2007,156-167 3. Young-soo Kim et. al, Crystal Growth & Design, Vol. 4, 2004,1211-1216

Purpose: To examine the potential to engineer a new formulation platform for delivering biomolecules to the lung: a design of experiments approach to determine the impact of adding amino acids (leucine, glycine and alanine) on the dispersibility and morphology of a mannitol-based spray-dried powder formulation. Methods: A range of compositions comprising mannitol and varying amino acids were spray-dried. A 2³ factorial design in which 3 amino acids selected for varying hydrocarbon chain length were added to control specific properties of the formulations. The aerosolisation efficiency was assessed by dispersing the powders from a Monodose inhaler into a Spraytec laser diffraction system. The morphology of the particles was examined under scanning electron microscope (SEM). Results: The mannitol had a median volume equivalent diameter of 2.8 (±0.1) µm while the formulations containing amino acid additives were mostly larger in laser diffraction measured diameter, although the DoE central point formulations containing leucine, glycine and alanine as additives demonstrated the smallest median diameter of 2.4 (±0.3) µm. The particles containing leucine, with or without others provided relatively efficient aerosolisation, but particle shape revealed distinctive morphological features. However, particles with alanine and/or glycine were more substantially agglomerated, and less easily dispersed. Conclusion: This DoE approach clearly identified the beneficial impact of inclusion of leucine on the aerosol performance and morphology of the formulations. The benefit provided by the leucine appears associated with its enrichment at the particle surface, as well as impact on particle morphology.

The use of magnetic resonance imaging (MRI) as a tool in pharmaceutical research dates back to the early 1990s where traditional spin-echo magnetic resonance imaging was to investigate the swelling of hydrating hydroxypropylmethylcellulose (HPMC) tablets. Since then there has been a vast amount of work published in the literature concerning the use of magnetic resonance imaging and its application to pharmaceutical systems. However, many of these previous studies were not fully quantitative and generally only gave qualitative information. The aim of this paper is to focus on the use of state-of-the art fast quantitative magnetic resonance techniques and how they are used to extract quantitative information that is of direct relevance to pharmaceutical research. The paper will focus on the application of fast multi-nuclear quantitative MRI techniques to study the dynamics of tablet dissolution, drug mobilisation and tablet erosion in a standard USP-4 dissolution cell operated under bio-relevant conditions. We show that it is possible to obtain two-dimensional spatially resolved maps within the tablet in less than two minutes. We demonstrate it is possible to obtain local information, within the tablet, regarding dissolution media concentration, dissolution media hydrodynamics and both Fickian and self-diffusion transport coefficients. In addition, we show it is also possible, through multi-nuclear MRI, to gain new insights into drug mobilisation within a tablet during the dissolution process.