Karin Kogermann

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.

Establishing quantitative in-line analysis of multiple solid-state transformations during dehydration

The aim of the study was to conduct quantitative solid phase analysis of piroxicam (PRX) and carbamazepine (CBZ) during isothermal dehydration in situ, and additionally exploit the constructed quantitative models to analyze the solid-state forms in-line during fluidized bed drying. Vibrational spectroscopy (near-infrared (NIR), Raman) was employed for monitoring the dehydration and the quantitative model was based on partial least squares (PLS) regression. PLS quantification was confirmed experimentally using isothermal thermogravimetric analysis (TGA) and X-ray powder diffractometry (XRPD). To appraise the quality of quantitative models several model parameters were evaluated. The hot-stage spectroscopy quantification results were found to be in reasonable agreement with TGA and XRPD results. Quantification of PRX forms showed complementary results with both spectroscopic techniques. The solid-state forms observed during CBZ dihydrate dehydration were quantified with Raman spectroscopy, but NIR spectroscopy failed to differentiate between the anhydrous solid-state forms of CBZ. In addition to in situ dehydration quantification, Raman spectroscopy in combination with PLS regression enabled in-line analysis of the solid-state transformations of CBZ during dehydration in a fluidized bed dryer.

Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs.

Electrospinning was introduced as a novel technique for preparing controlled-release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR-SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid-state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR-SD nanofibers ranged from 400 to 600 nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6-8 °C/0% RH) and ambient room temperature (22 °C/0% RH). At higher temperature and humidity (30 °C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR-SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR-SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX.

Investigating Dehydration from Compacts Using Terahertz Pulsed, Raman, and Near-Infrared Spectroscopy

The purpose of this study was to investigate the dehydration of piroxicam monohydrate (PRXMH) in compacts using terahertz pulsed spectroscopy (TPS), Raman spectroscopy, and reflectance near-infrared (NIR) spectroscopy. Compacts were prepared by using PRXMH and poly(tetrafluoro)ethylene powders and combining them in three different manners before compression to produce compacts in which the PRXMH was dispersed throughout the compact, deposited on one face of the compact, or included as a layer within the compact. TPS was a suitable technique to assess the effect of sample preparation on dehydration, whereas Raman and NIR spectroscopy were limited by their sampling depth and the interference of the polymer matrix. TPS revealed that the dehydration behavior depended largely on the compact preparation method. Non-isothermal dehydration was investigated with all three spectroscopic techniques, combined with principal component analysis (PCA) on samples where the PRXMH was deposited on one face of the compact. In addition, variable temperature X-ray powder diffractometry (VT-XRPD) was used to verify the transformation from PRXMH to anhydrous PRX form I, while thermogravimetric analysis (TGA) was used to monitor the water loss. All three spectroscopic techniques allowed in situ monitoring of the dehydration from the surface layers of the compacts. TPS and Raman spectroscopy detected structural changes of the crystal, while NIR spectroscopy was more sensitive to water loss. PCA of the TPS, Raman spectroscopy, and XRPD data revealed similar dehydration profiles. In contrast, the NIR spectroscopy profile was more similar to the TGA results. The spectroscopic techniques were more suitable than slower techniques such as VT-XRPD for monitoring rapid structural changes that occurred during the dehydration.

Amorphous solid dispersions of piroxicam and Soluplus®: Qualitative and quantitative analysis of piroxicam recrystallization during storage

The conversion of active pharmaceutical ingredient (API) from amorphous to crystalline form is the primary stability issue in formulating amorphous solid dispersions (SDs). The aim of the present study was to carry out qualitative and quantitative analysis of the physical solid-state stability of the SDs of poorly water-soluble piroxicam (PRX) and polyvinyl caprolactam-polyvinyl acetate-polyethylene-glycol graft copolymer (Soluplus(®)). The SDs were prepared by a solvent evaporation method and stored for six months at 0% RH/6 °C, 0% RH/25 °C, 40% RH/25 °C and 75% RH/25 °C. Fourier transform infrared spectroscopy equipped with attenuated total reflection accessory (ATR-FTIR) and Raman spectroscopy were used for characterizing the physical solid-state changes and drug-polymer interactions. The principal component analysis (PCA) and multivariate curve resolution alternating least squares (MCR-ALS) were used for the qualitative and quantitative analysis of Raman spectra collected during storage. When stored at 0% RH/6 °C and at 0% RH/25 °C, PRX in SDs remained in an amorphous form since no recrystallization was observed by ATR-FTIR and Raman spectroscopy. Raman spectroscopy coupled with PCA and MCR-ALS and ATR-FTIR spectroscopy enabled to detect the recrystallization of amorphous PRX in the samples stored at higher humidity.

Dissolution testing of amorphous solid dispersions.

The main purpose of this study was to investigate the effect of different polymers, with varying physicochemical properties and molecular weight on the stability and dissolution of co-milled amorphous solid dispersions (ASDs) of piroxicam (PRX). The stability of amorphous PRX (aPRX) in ASDs was significantly improved by the polymers. In-line Raman spectroscopy revealed that solvent mediated solid state changes occurred in biorelevant medium, however differences between ASDs were found. Thus, the dissolution behavior of ASDs of PRX and the respective polymer during conventional large volume (900ml) and a commercial small volume (20ml) dissolution testing was evaluated. The results of these studies indicated that the molecular weight of the polymer (PVP90 vs PVP25) is influencing the solubility of PRX from ASD. Interestingly the effect of molecular weight of the polymer was different than reported previously in the literature for the similar ASDs prepared by spray drying. Furthermore, the dose related bioavailability was determined by investigating the experimental saturation concentrations for different doses. These studies confirmed the findings of the dissolution studies. The differences are presumably caused by the formation of physically different diffusion layers around the ASD particles.

Solid-state dependent dissolution and oral bioavailability of piroxicam in rats.

The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats. Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD). In addition, the effect of a new polymeric excipient Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated. Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam. Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium. Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats. Oral bioavailability of other two solid-state forms decreased in the order AH and MH. The use of Soluplus® was found to enhance the dissolution and oral bioavailability of piroxicam in rats. The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug.

Soluplus Graft Copolymer: Potential Novel Carrier Polymer in Electrospinning of Nanofibrous Drug Delivery Systems for Wound Therapy

Electrospinning is an effective method in preparing polymeric nanofibrous drug delivery systems (DDSs) for topical wound healing and skin burn therapy applications. The aim of the present study was to investigate a new synthetic graft copolymer (Soluplus) as a hydrophilic carrier polymer in electrospinning of nanofibrous DDSs. Soluplus (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)) was applied in the nonwoven nanomats loaded with piroxicam (PRX) as a poorly water-soluble drug. Raman spectroscopy, X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy (SEM) were used in the physical characterization of nanofibrous DDSs. According to the SEM results, the drug-loaded PCL-PVAc-PEG nanofibers were circular in cross-section with an average diameter ranging from 500 nm up to 2 µm. Electrospinning stabilized the amorphous state of PRX. In addition, consistent and sustained-release profile was achieved with the present nanofibrous DDSs at the physiologically relevant temperature and pH applicable in wound healing therapy. In conclusion, electrospinning can be used to prepare nanofibrous DDSs of PCL-PVAc-PEG graft copolymer (Soluplus) and to stabilize the amorphous state of a poorly water-soluble PRX. The use of this synthetic graft copolymer can open new options to formulate nanofibrous DDSs for wound healing.

Insight into the solubility and dissolution behavior of piroxicam anhydrate and monohydrate forms

The aim of the present study was two-fold: (1) to investigate the effect of pH and presence of surfactant sodium lauryl sulphate (SLS) on the solubility and dissolution rate of two solid-state forms of piroxicam (PRX), anhydrate (PRXAH) and monohydrate (PRXMH), and (2) to quantitatively assess the solid-phase transformation of PRXAH to PRXMH in slurry with a special interest to the impact on the solubility and dissolution behavior of the drug. X-ray powder diffractometry (XRPD), Raman spectroscopy and scanning electron microscopy (SEM) were used for characterization of the solid-state forms. Phase transformation was monitored in slurry by means of in-line Raman spectroscopy, and the partial least squares (PLS) regression model was used for predicting the amount of PRXMH. The results showed that the solubility and dissolution rate of PRXAH were higher compared to PRXMH at different pHs. The pH and presence of SLS together affected the solubility and dissolution rate of different PRX forms. The lowest solubility values and dissolution rates for PRX forms were observed in distilled water (pH 5.6) at 37 °C. The changes in the dissolution rate could be explained by the hydrate formation during solubility testing. The rate of hydrate formation was also dependent on the pH of the dissolution medium.

Polymorphic form of piroxicam influences the performance of amorphous material prepared by ball-milling.

The objective of this study was to investigate the influence of the starting solid state form of piroxicam (anhydrate form I: PRXAH I vs form II: PRXAH II) on the properties of the resulting amorphous material. The second objective was to obtain further insight into the impact of critical factors like thermal stress, dissolution medium and storage conditions on the thermal behavior, solid state transformations and physical stability of amorphous materials. For analysis differential scanning calorimetry (DSC), Raman spectroscopy and X-ray powder diffractometry (XRPD) were used. Pair-wise distribution function (PDF) analysis of the XRPD data was performed. PDF analysis indicated that the recrystallization behavior of amorphous samples was influenced by the amount of residual order in the samples. The recrystallization behavior of amorphous samples prepared from PRXAH I showed similarity to the starting material, whereas the recrystallization behavior of amorphous samples prepared from PRXAH II resembled to that of the PRX form III (PRXAH III). Multivariate data analysis (MVDA) helped to identify that the influence of storage time and temperature was more pronounced in the case of amorphous PRX prepared from PRXAH I. Furthermore, the wet slurry experiments with amorphous materials revealed the recrystallization of amorphous material as PRXMH in the biorelevant medium.