Anna Jørgensen

Hydrate Formation During Wet Granulation Studied by Spectroscopic Methods and Multivariate Analysis

AbstractPurpose. The aim was to follow hydrate formation of two structurally related drugs, theophylline and caffeine, during wet granulation using fast and nondestructive spectroscopic methods. Methods. Anhydrous theophylline and caffeine were granulated with purified water. Charge-coupled device (CCD) Raman spectroscopy was compared with near-infrared spectroscopy (NIR) in following hydrate formation of drugs during wet granulation (off-line). To perform an at-line process analysis, the effect of water addition was monitored by NIR spectroscopy and principal components analysis (PCA). The changes in the crystal arrangements were verified by using X-ray powder diffraction (XRPD). Results. Hydrate formation of theophylline and caffeine could be followed by CCD Raman spectroscopy. The NIR and Raman spectroscopic results were consistent with each other. NIR revealed the state of water, and Raman spectroscopy gave information related to the drug molecule itself. The XRPD confirmed the spectroscopic results. PCA with three principal components explained 99.9of the spectral variation in the second derivative NIR spectra. Conclusions. Both CCD Raman and NIR spectroscopic methods can be applied to monitoring of hydrate formation processes. However, NIR is more suitable for monitoring solid-water interactions.

Novel Identification of Pseudopolymorphic Changes of Theophylline During Wet Granulation Using Near Infrared Spectroscopy

The purpose of this study was to demonstrate the efficiency of near infrared (NIR) spectroscopy in studying the pseudopolymorphic changes and the state of water during the wet granulation process. Anhydrous theophylline was granulated in a planetary mixer using water as granulation liquid. NIR spectra and differential scanning calorimetric (DSC) and wide-angle X-ray scattering (WAXS) patterns of theophylline granules, anhydrous theophylline, and theophylline monohydrate were measured. At a low level of granulation liquid (0.3 mol of water per mole of anhydrous theophylline), water absorption maxima in the NIR region occurred first at around 1475 and 1970 nm. These absorption maxima were identical to those of theophylline monohydrate. At higher levels of granulation liquid (1.3-2.7 mol of water per mole of anhydrous theophylline), the increasing absorption maxima occurred at 1410 and 1905 nm due to OH vibrations of free water molecules. X-ray diffraction patterns confirmed the transformation of anhydrous theophylline to theophylline monohydrate during wet granulation. NIR spectroscopy was able to detect different states of water molecules during the wet granulation process faster and in a more flexible manner than conventional methods.

Solid-State and Mechanical Properties of Aqueous Chitosan-Amylose Starch Films Plasticized With Polyols

The film-forming ability of chitosan and binary mixtures of chitosan and native amylose corn starch (Hylon VII) was evaluated with free films prepared by a casting/solvent evaporation method. Unplasticized and plasticized free chitosan films in aqueous acetic acid and respective films containing a mixture of chitosan and native amylose starch in acetic acid were prepared. Glycerol, sorbitol, and i-erythritol were used as plasticizers. Solid-state and mechanical properties of the films were studied by powder x-ray diffractometry (XPRD), differential scanning calorimetry (DSC), and a materials testing machine. The films composed of a mixture of chitosan and native amylose starch in acetic acid were clear and colorless. A plasticizer concentration of 20% wt/wt (of the polymer weight) ws sufficient to obtain flexible films with all samples tested. X-ray diffraction patterns and DSC thermograms indicated an amorphous state of the films independent of the type of plasticizer used. In conclusion, incorporation of native amylose com starch into chitosan films improves the consistency and the mechanical properties of the films.

Process analysis of fluidized bed granulation.

This study assesses the fluidized bed granulation process for the optimization of a model formulation using in-line near-infrared (NIR) spectroscopy for moisture determination. The granulation process was analyzed using an automated granulator and optimization of the verapamil hydrochloride formulation was performed using a mixture design. The NIR setup with a fixed wavelength detector was applied for moisture measurement. Information from other process measurements, temperature difference between process inlet air and granules (Tdiff), and water content of process air (AH), was also analyzed. The application of in-line NIR provided information related to the amount of water throughout the whole granulation process. This information combined with trend charts of Tdiff and AH enabled the analysis of the different process phases. By this means, we can obtain in-line documentation from all the steps of the processing. The choice of the excipient affected the nature of the solid-water interactions; this resulted in varying process times. NIR moisture measurement combined with temperature and humidity measurements provides a tool for the control of water during fluid bed granulation.

Factors affecting crystallization of hydrates.

Objectives  To provide a comprehensive understanding of the competing thermodynamic and kinetic factors governing the crystallization of various hydrate systems. The ultimate goal is to utilize this understanding to improve the control over the unit operations involving hydrate formation, as well as to optimize the bioavailability of a given drug product.

An insight into water of crystallization during processing using vibrational spectroscopy

Many organic molecules used as drugs can incorporate water into their crystal lattice. These compounds are also prone to processing-induced transformations (PITs) because processing often exposes the compounds to moisture, heat and mechanical stress. The aim of this review is to provide an overview of the possibilities for following and understanding hydrate/anhydrate transformations using vibrational spectroscopy (mid-infrared, near-infrared, Raman and terahertz). The review begins with a general section on hydrates, followed by considerations on the impact of these on drug products and a description of transformation mechanisms of hydrates. Moreover, a general introduction is given for the spectroscopic techniques together with a discussion of critical issues for quantification models. Unit operations that may induce transformations in hydrate systems are discussed with focus on the published work on the use of spectroscopy to derive information from these processes. Finally, the effect of excipients on PITs is discussed.

Humid Storage Conditions Increase the Dissolution Rate of Diazepam from Solid Dispersions Prepared by Melt Agglomeration

The purpose of this study is to investigate the effect of cooling mode and storage conditions on the dissolution rate of a solid dispersion prepared by melt agglomeration. The aim has been to relate this effect to the solid state properties of the agglomerates. The cooling mode had an effect on the dissolution rate, probably due to several factors such as the morphology of the agglomerates and crystallinity of the carrier. The dissolution increased with increasing temperature and relative humidity which increased the amount of water sorbed in the carrier. The processing and storage conditions were shown to have a complex interplay.

The influence of thermal history on the physical behavior of poly(ethylene glycol) (PEG)

Objectives: To investigate the influence of thermal history on the physical behavior of poly(ethylene glycol) (PEG), commonly used as a pharmaceutical excipient. Materials and methods: Rheological investigations together with SEM imaging and solid state analysis by XRPD and DSC were used to characterize PEG as starting material, as well as PEG:lactose monohydrate granules. For granulation experiments PEG 6000 was used and for further investigations of physicochemical properties, three Mw of PEG (3000–10000) with different thermal histories obtained by melting the PEG followed by solidification with specific cooling rates. Results and discussion: More uniform granules were obtained when fast cooled PEG was used as binder. XRPD suggested similar crystallinity for the different Mw and thermal history did not influence the results drastically. However, rheological analysis and DSC measurements indicated different melting behavior dependent on the Mw of PEG. PEG 6000 and 10000 were affected by the thermal treatment where stepwise melting was observed with slower cooling rate probably due to increased formation of extended structures. Conclusions: Increased cooling rate gives rise to increased randomness, more folded structure of PEG, which reflects in the outcome of the granulation process.