Analysis of matrix dosage forms during dissolution testing using raman microscopy

Matrix dosage forms are widely used for sustained drug release. As both the distribution of the matrix components and physical changes during dissolution can impact drug release behavior, a comprehensive investigation of these phenomena is required during matrix development. In this study, Raman microscopy was used to investigate different extrudate formulations in terms of component distribution and structural changes during dissolution testing. Two systems containing the model drug theophylline anhydrate were investigated: a binary system, based on a tripalmitin matrix, and a ternary system, containing tripalmitin and polyethylene glycol. The distribution of the drug and the soluble and insoluble matrix components were mapped during dissolution testing. Although a receding drug boundary was observed, it was not uniformly distant from the matrix edge. The lipid structure remained intact, whereas the water‐soluble polymer rapidly dissolved and diffused from the matrix leaving a more extensive network of channels through which the dissolution medium could penetrate and the drug could diffuse. Raman mapping can be considered a useful aid in the direct analysis of multiple matrix components during drug release, and therefore a deeper understanding of factors affecting drug release can be obtained during the development of sustained‐release matrices. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4452–4459, 2011     

Budesonide Loaded PLGA Nanoparticles for Targeting the Inflamed Intestinal Mucosa—Pharmaceutical Characterization and Fluorescence Imaging

Purpose

The purpose of this study was to evaluate the specifically targeted efficiency of budesonide loaded PLGA nanoparticles for the treatment of inflammatory bowel disease (IBD).

Methods

The nanoparticles were prepared by an oil/water (O/W) emulsion evaporation technique. The nanoparticles were characterized for their size, shape and in vitro drug release profile. Solid state characterization was carried out by differential scanning calorimetry (DSC) and X-ray Power diffraction (XPRD). In order to evaluate the targeted efficiency of nanoparticles, a particle localization study in the healthy and in the inflamed colon was determined in vivo. These data were complemented by cryo-sections.

Results

Nanoparticles were 200?±?05 nm in size with a smooth and spherical shape. The encapsulation efficiency was around 85?±?3.5%, which was find-out by both, direct and indirect methods. Release of budesonide from the nanoparticles showed a biphasic release profile with an initial burst followed by sustained release. XPRD data revealed that the drug in the polymer matrix existed in crystalline state. Nanoparticles accumulation in inflamed tissues was evaluated by in-vivo imaging system and it was found that particles are accumulated in abundance at the site of inflammation when compared to the healthy group.

Conclusion

The study demonstrates that the budesonide loaded PLGA nanoparticles are an efficient delivery system for targeted drug delivery to the inflamed intestinal mucosa.

     

Freeze‐drying as a preserving preparation technique for in vitro testing of human skin

In vitro testing of drugs with excised human skin is a valuable prerequisite for clinical studies. However, the analysis of excised human skin presents several obstacles. Ongoing drug diffusion, microbial growth and changes in hydration state influence the results of drug penetration studies. In this work, we evaluate freeze‐drying as a preserving preparation method for skin samples to overcome these obstacles. We analyse excised human skin before and after freeze‐drying and compare these results with human skin in vivo. Based on comprehensive thermal and spectroscopic analysis, we demonstrate comparability to in vivo conditions and exclude significant changes within the skin samples due to freeze‐drying. Furthermore, we show that freeze‐drying after skin incubation with drugs prevents growth of drug crystals on the skin surface due to drying effects. In conclusion, we introduce freeze‐drying as a preserving preparation technique for in vitro testing of human skin.     

Application of Confocal Raman Microscopy for the Characterization of Topical Semisolid Formulations and their Penetration into Human Skin Ex Vivo

Pharmaceutical Research - The quality testing and approval procedure for most pharmaceutical products is a streamlined process with standardized procedures for the determination of critical quality...     

Investigating the relationship between drug distribution in solid lipid matrices and dissolution behaviour using raman spectroscopy and mapping

In this study, in situ and mapping Raman spectroscopic measurements were used to investigate the physical structure of solid lipid extrudates and relate the structure to dissolution behaviour. Theophylline anhydrate was extruded with tripalmitin, with and without the water‐soluble polymer, polyethylene glycol 10000. Raman mapping of the extrudate cores revealed that drug particles of diverse size were dispersed in a continuous lipid phase with or without polyethylene glycol. At the surface, there was evidence of more mixing between the components. Previous characterisation by other methods suggested that the extrudate surface is covered predominantly by lipid, and the Raman mapping suggested that such a layer is in general less than a few micrometres thick. Nevertheless, the lipid layer dramatically reduced the drug dissolution rate. The extrudate cores were also mapped after a period of dissolution testing, and there was no evidence of a uniformly receding drug boundary in the extrudates during drug release. In situ Raman spectroscopy analysis during dissolution testing revealed that the drug distribution in the extrudate affected the formation of theophylline monohydrate. However, the drug release rate was primarily determined directly by drug distribution, with the solid‐state behaviour of the drug having a smaller influence. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1464–1475, 2010     

Preparation,characterisation and in vitro antibacterial property of ciprofloxacin-loaded nanostructured lipid carrier for treatment of Bacillus subtilis infection

Context: In this study, controlled ciprofloxacin (CIPRO) nanostrustructured lipid carriers of Precirol^® ATO 5/Transcutol^® HP (batch A) and tallow fat/Transcutol^® HP (batch B) was carreid out. Objective: The aim was to improve solubility and bioavailability of CIPRO.

Objective: Study of controlled ciprofloxacin (CIPRO) nanostructured lipid carriers of Precirol^® ATO 5/Transcutol^® HP (batch A) and tallow fat/Transcutol^® HP (batch B).

Methods: CIPRO concentrations C_1–5 (0.0, 0.2, 0.5, 0.8, and 1.0% w/w) as AC_1–5 and BC_1–5 were prepared by hot homogenisation and characterised by zetasizer, differential scanning calorimetry, Fourier transform infra-red spectroscopy, in vitro drug release and growth inhibitory zone diameter (IZD) on agar-seeded Bacillus subtilis.

Results: AC₅ achieved polydispersed particles of ～605?nm, 92% encapsulation efficiency (EE) and –28?mV similar to BC₅ (～789?nm, 91% EE, and –31?mV). Crystallinity indices (AC₅ and BC₅) were low at 3 and 5%, respectively. CIPRO release in AC₅ was ～98% in SGF (pH 1.2) and BC₅ similarly ～98% in SIF (pH 6.8).

Conclusions: AC₅ had superior growth inhibition of B. subtilis at lower concentration (1.2 µg/mL) than BC₅ and CIPRO controls; hence could serve as possible sustained delivery system of CIPRO.     

Combining confocal Raman microscopy and freeze‐drying for quantification of substance penetration into human skin

In the area of dermatological research, the knowledge of rate and extent of substance penetration into the human skin is essential not only for evaluation of therapeutics, but also for risk assessment of chemicals and cosmetic ingredients. Recently, confocal Raman microscopy emerged as a novel analytical technique for analysis of substance skin penetration. In contrast to destructive drug extraction and quantification, the technique is non‐destructive and provides high spatial resolution in three dimensions. However, the generation of time‐resolved concentration depth profiles is restrained by ongoing diffusion of the penetrating substance during analysis. To prevent that, substance diffusion in excised human skin can instantly be stopped at defined time points by freeze‐drying the sample. Thus, combining sample preparation by freeze‐drying with drug quantification by confocal Raman microscopy yields a novel analytical platform for non‐invasive and quantitative in vitro analysis of substance skin penetration. This work presents the first proof‐of‐concept study for non‐invasive quantitative substance depth profiling in freeze‐dried excised human stratum corneum by confocal Raman microscopy.     

Solid Dispersions Prepared by Continuous Cogrinding in an Air Jet Mill

Embedding a poorly water-soluble drug as a solid dispersion in a hydrophilic carrier by cogrinding is a possible strategy for enhancing the drug dissolution rate. Although general interest in continuous processes for manufacturing drug formulations has increased, many publications still focus on batch processes. The jet mill used in this study is a promising tool for continuous cogrinding. Investigation of different drug-to-carrier ratios (griseofulvin/mannitol) demonstrated that a drug load of 10% is best suited to investigate the enhanced dissolution behavior. To gain deeper insight into the underlying mechanisms, the coground dispersion is compared with different physical mixtures in terms of physicochemical properties and dissolution behavior. Differential scanning calorimetry and X-ray powder diffraction were used to verify the crystalline structure of the coground formulation. On the basis of the Hixson-Crowell model, particle size reduction was ruled out as the main reason for dissolution enhancement. An increase of surface free energies because of grinding is shown with contact angle measurements. Confocal Raman microscopy investigations revealed the drug's bulk dispersity in the coground formulation as an additional factor for the increased dissolution rate. In conclusion, the continuous cogrinding approach is a promising technique to prepare the drug in a rapidly dissolving, yet crystalline, form.     

Understanding the solid-state behaviour of triglyceride solid lipid extrudates and its influence on dissolution

Three monoacid triglycerides differing in their fatty acid chain lengths were extruded below their melting temperatures. Physical characterization was conducted on the powders as well as the extrudates with a combination of DSC, XRPD and vibrational spectroscopy to get a deeper insight into the complex solid-state behaviour of lipids and solid lipid extrudates during processing and storage. The combination of extrusion temperature and friction was a key factor for the lipid polymorphic behaviour after extrusion. Polymorphic transitions had a strong influence on the dissolution behaviour due to crystallization of the stable β-form from the unstable α-form on the surface of the extrudate. These correlations help to understand the solid-state behaviour of lipids and to avoid process conditions which lead to unstable dosage forms. Tailor-made dissolution profiles for a model drug could be achieved using triglycerides of different fatty acid chain lengths as the dissolution rate is chain-length dependent. The solid-state form of the drug was unchanged after storage in accelerated conditions over 10 months. These studies demonstrate that although triglycerides are a promising basis for oral dosage forms, a good understanding and monitoring of the solid-state behaviour is mandatory to obtain reliable and reproducible dosage forms.     

Chemical Imaging of Drug Delivery Systems with Structured Surfaces–a Combined Analytical Approach of Confocal Raman Microscopy and Optical Profilometry

Confocal Raman microscopy is an analytical technique with a steadily increasing impact in the field of pharmaceutics as the instrumental setup allows for nondestructive visualization of component distribution within drug delivery systems. Here, the attention is mainly focused on classic solid carrier systems like tablets, pellets, or extrudates. Due to the opacity of these systems, Raman analysis is restricted either to exterior surfaces or cross sections. As Raman spectra are only recorded from one focal plane at a time, the sample is usually altered to create a smooth and even surface. However, this manipulation can lead to misinterpretation of the analytical results. Here, we present a trendsetting approach to overcome these analytical pitfalls with a combination of confocal Raman microscopy and optical profilometry. By acquiring a topography profile of the sample area of interest prior to Raman spectroscopy, the profile height information allowed to level the focal plane to the sample surface for each spectrum acquisition. We first demonstrated the basic principle of this complementary approach in a case study using a tilted silica wafer. In a second step, we successfully adapted the two techniques to investigate an extrudate and a lyophilisate as two exemplary solid drug carrier systems. Component distribution analysis with the novel analytical approach was neither hampered by the curvature of the cylindrical extrudate nor the highly structured surface of the lyophilisate. Therefore, the combined analytical approach bears a great potential to be implemented in diversified fields of pharmaceutical sciences.