Marja Savolainen

Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy

Amorphous drugs have a higher kinetic solubility and dissolution rate than their crystalline counterparts. However, this advantage is lost if the amorphous form converts to the stable crystalline form during the dissolution as the dissolution rate will gradually change to that of the crystalline form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant analysis (PLS-DA) or partial least squares (PLS) regression analysis to monitor as well as quantify the solid-phase transitions that take place during the dissolution of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline alpha- and gamma-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point the sample started to crystallize to the alpha-form. Amorphous CBZ instantly started to crystallize upon contact with the dissolution medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS analysis the amount of form I formed in the sample during the dissolution affected the dissolution rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.

Evaluation of controlled-release polar lipid microparticles

The aim of the present study was to prepare controlled-release tablets of poorly-soluble drug, felodipine, and various erodable lipophilic excipients. Spray chilling was used to formulate the drug and the excipients into solid dispersion microparticles, which were then compressed. The microparticles were characterised by Fourier transform infrared spectroscopy, hot-stage microscopy, scanning electron microscopy, and image analysis. The amine and the carbonyl groups of felodipine formed hydrogen bonds with the carriers. The shape of the particles was spherical with the median particle diameter ranging from 25 to 35 microm. Surprisingly, the degree of crystallinity in felodipine and the ease of tablet disintegration played a more significant role on the felodipine dissolution rate than the matrix lipophilicity. Felodipine release rate was slowest from the least lipophilic tablets.

Insights into the Early Dissolution Events of Amlodipine Using UV Imaging and Raman Spectroscopy

Traditional dissolution testing determines drug release to the bulk, but does not enable an understanding of the events happening close to the surface of a solid or a tablet. UV imaging is a new imaging approach that can be used to study the dissolution behavior of chemical compounds. The UV imaging instrumentation offers recording of absorbance maps with a high spatial and temporal resolution which facilitates the abundant collection of information regarding the evolving solution concentrations. In this study, UV imaging was used to visualize the dissolution behavior of amlodipine besylate (amorphous and dihydrate forms) and amlodipine free base. The dissolution of amlodipine besylate was faster from the amorphous form than from the crystalline forms. The UV imaging investigations suggested that a solvent mediated phase transformation occurred for the amorphous amlodipine besylate and the amlodipine free base samples. Raman spectroscopy was used to confirm and probe the changes at the solid surface occurring upon contact with the dissolution media and verified the recrystallization of the amorphous form to the monohydrate. The combination of UV imaging and Raman spectroscopy is an efficient tool to obtain a deeper insight into the early events of the dissolution process.

Evaluation of polar lipid–hydrophilic polymer microparticles

The aim of the present study was to prepare controlled-release tablets of poorly-soluble drug, felodipine. Spray chilling was used to formulate the drug, the polar lipids and the hydrophilic polymers into solid dispersion microparticles, which were then compressed. The microparticles were characterised by Fourier transform infrared and Raman spectroscopies, X-ray powder diffraction, hot-stage microscopy, scanning electron microscopy, and image analysis. The crystallinity of felodipine had decreased in all the samples, and the amount of crystalline felodipine varied depending on the composition of the solid dispersion. The particles were spherical with the median particle diameter ranging from 20 to 35 microm. The addition of hydrophilic polymer into the matrix widened the particle size distribution and increased the amount of agglomerates. Most promising dissolution patterns were obtained from tablets containing glycerides; e.g. from Precirol ATO 5/Pluronic F127 tablets the release was of zero order.

Determination of amorphous content in the pharmaceutical process environment.

The amorphous state has different chemical and physical properties compared with a crystalline one. Amorphous regions in an otherwise crystalline material can affect the bioavailability and the processability. On the other hand, crystalline material can function as nuclei and decrease the stability of an amorphous system. The aim of this study was to determine amorphous content in a pharmaceutical process environment using near infrared (NIR) and Raman spectroscopic techniques together with multivariate modelling tools. Milling was used as a model system for process‐induced amorphization of a crystalline starting material, α‐lactose monohydrate. In addition, the crystallization of amorphous material was studied by storing amorphous material, either amorphous lactose or trehalose, at high relative humidity conditions. The results show that both of the spectroscopic techniques combined with multivariate methods could be applied for quantitation. Preprocessing, as well as the sampling area, was found to affect the performance of the models. Standard normal variate (SNV) transformation was the best preprocessing approach and increasing the sampling area was found to improve the models. The root mean square error of prediction (RMSEP) for quantitation of amorphous lactose using NIR spectroscopy was 2.7%, when a measuring setup with a larger sampling area was used. When the sampling area was smaller, the RMSEPs for lactose and trehalose were 4.3% and 4.2%, respectively. For Raman spectroscopy, the RMSEPs were 2.3% and 2.5% for lactose and trehalose, respectively. However, for the optimal performance of a multivariate model, all the physical forms present, as well as the process environment itself, have to be taken into consideration.

Atomic Pairwise Distribution Function Analysis of the Amorphous Phase Prepared by Different Manufacturing Routes

Amlodipine besilate, a calcium channel antagonist, exists in several solid forms. Processing of anhydrate and dihydrate forms of this drug may lead to solid state changes, and is therefore the focus of this study. Milling was performed for the anhydrate form, whereas the dihydrate form was subjected to quench cooling thereby creating an amorphous form of the drug from both starting materials. The milled and quench cooled samples were, together with the crystalline starting materials, analyzed with X-ray powder diffraction (XRPD), Raman spectroscopy and atomic pair-wise distribution function (PDF) analysis of the XRPD pattern. When compared to XRPD and Raman spectroscopy, the PDF analysis was superior in displaying the difference between the amorphous samples prepared by milling and quench cooling approaches of the two starting materials.