Mike Reading

Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions: Etravirine

Solid dispersion technology represents an enabling approach to formulate poorly water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to an increased drug dissolution rate, amorphous dispersions can be limited by their physical stability. The ability to assess formulation risk in this regard early in development programs can not only help in guiding development strategies but can also point to critical design elements in the configuration of the dosage form. Based on experience with a recently approved solid dispersion-based product, Intelence® (etravirine), a three part strategy is suggested to predict early formulate-ability of these systems. The components include an assessment of the amorphous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug and polymer processed in a manner relevant to the intended final dosage form. A variety of thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the prepared materials. The data suggest a correlation between the glass forming ability and stability of the amorphous drug and the nature of the final formulation. Cast films can provide early information on miscibility and stabilization and assessment of processed powders can help define requirements and identify issues with potential final formulations.

Thermal Analysis of Pharmaceuticals

As a result of the Process Analytical Technologies (PAT) initiative launched by the U.S. Food and Drug Administration (FDA), analytical development is receiving more attention within the pharmaceutical industry. Illustrating the importance of analytical methodologies, Thermal Analysis of Pharmaceuticals presents reliable and versatile characterization tools for the successful development of pharmaceutical products. It draws attention to the most widely applicable methods and demonstrates how to interpret the associated data.The book opens with the first three chapters devoted to differential scanning calorimetry (DSC), the most commonly used thermal method. These chapters cover the principles, optimal use, and pharmaceutical applications of the method. Subsequent chapters explore modulated temperature DSC, thermogravimetric analysis, thermal microscopy, microcalorimetry, high sensitivity DSC, dynamic mechanical analysis, and thermally stimulated current, all of which have attracted great interest within the pharmaceutical field. The chapters include theoretical background, measurement optimization, and pharmaceutical applications of each technique.Exploring important techniques for characterizing the physical structure and properties of pharmaceutical materials, Thermal Analysis of Pharmaceuticals achieves an ideal balance in the depth, relevance, and accessibility of topics presented. The book provides an excellent overview of this key area in pharmaceutical development.

Characterisation and prediction of phase separation in hot-melt extruded solid dispersions: a thermal, microscopic and NMR relaxometry study.

ABSTRACTPurposeTo develop novel analytical approaches for identifying both miscibility and phase separation in hot-melt extruded formulations.MethodsFelodipine-Eudragit® E PO solid dispersions were prepared using hot-melt extrusion. The fresh and aged formulations were characterised using scanning electron microscopy, differential scanning calorimetry, heat capacity (Cp) measurements using modulated temperature DSC and nuclear magnetic resonance relaxometry.ResultsThe solubility of the drug in polymer was predicted as being ≤10% w/w using a novel model proposed in this study. Freshly prepared HME formulations were found to show no evidence for phase separation despite drug loadings greatly in excess of this figure. Conventional DSC showed limitations in directly detecting phase separation. However, a novel use of Cp measurements indicated that extensive phase separation into crystalline domains was present in all aged samples, a conclusion supported by SEM studies. The NMR relaxometry study confirmed the existence of phase separation in all aged formulations and also allowed the estimation of separated domains sizes in different formulations.ConclusionsThis study has presented a series of novel approaches for the identification, quantification and prediction of phase separation in HME formulations. Supersaturation of drug in the polymer caused the phase separation of the aged felodipine-Eudragit® E PO formulations.

An investigation into the crystallisation behaviour of an amorphous cryomilled pharmaceutical material above and below the glass transition temperature

The aim of this study was to evaluate the glass transition and recrystallisation of a cryomilled drug, TMC125 (Etravirine), with particular emphasis on assessing the physical stability of the drug above and below the glass transition temperature. DSC (conventional, fast and modulated temperature) and variable temperature ATR-FTIR spectroscopy were employed to monitor the glass transition and crystallisation behaviour of the material. The isothermal crystallisation behaviour was investigated at temperatures below T(g). The humidity-induced crystallisation behaviour of the material was evaluated using dynamic vapour sorption (DVS). The glass transition (99 degrees C) was measured in isolation from the crystallisation process using fast DSC, while ATR-FTIR allowed identification of the polymorph formed on recrystallisation. At a heating rate of 0.2 degrees C/min, the onset temperature of the crystallisation exotherm (67 degrees C) was 32 degrees C below T(g). Evidence is presented for incomplete crystallisation under isothermal conditions. In conclusion, the study has ascertained the crystallisation profile of cryomilled Etravirine under both isothermal and scanning conditions, with the material showing marked physical instability below the measured T(g).

Nanoscale Characterisation and Imaging of Partially Amorphous Materials using Local Thermomechanical Analysis and Heated Tip AFM

PurposeThe purpose is to investigate the use of thermal nanoprobes in thermomechanical and heated tip pulsed force modes as novel means of discriminating between amorphous and crystalline material on a sub-micron scale.Materials and methodsIndometacin powder was compressed and partially converted into amorphous material. Thermal nanoprobes were used to perform localised thermomechanical analysis (L-TMA) and heated tip pulsed force mode imaging as a function of temperature.ResultsL-TMA with submicron lateral spatial resolution and sub-100xa0nm depth penetration was achieved, allowing us to thermomechanically discriminate between amorphous and crystalline material at a nanoscale for the first time. The amorphous and crystalline regions were imaged as a function of temperature using heated tip pulsed force AFM and a resolution of circa 50xa0nm was achieved. We are also able to observe tip-induced recrystallisation of the amorphous material.DiscussionThe study demonstrates that we are able to discriminate and characterise amorphous and crystalline regions at a submicron scale of scrutiny. We have demonstrated the utility of two methods, L-TMA and heated tip pulsed force mode AFM, that allow us to respectively characterise and image adjacent amorphous and crystalline regions at a nanoscale.ConclusionsThe study has demonstrated that thermal nanoprobes represent a novel method of characterising and imaging partially amorphous materials.

Thermal scanning probe microscopy in the development of pharmaceuticals

The ability to characterize the physical and chemical properties of dosage forms is crucial to a more complete understanding of how vehicles for drug delivery behave and therefore how effective they are. Spatially resolved characterization that enables the visualization of properties on the nanoscale is particularly powerful. The usefulness of scanning probe microscopy (SPM) in the field of drug delivery is becoming increasingly well established and the use of thermal probes offers new capabilities thus enabling SPM to provide more and sometimes unique information. One type of measurement enabled by thermal probes is determining transition temperatures by means of local thermal analysis. The ability to identify and characterize materials in this way has found applications in characterizing a wide range of dosage forms. A complimentary thermal probe technique is photothermal infrared microspectroscopy (PTMS). PTMS offers a variety of advantages over more conventional approaches including the ability analyze compacts without the need for thin sections. It is also able to achieve sub-micron spatial resolution. Thermal probe techniques can characterize pharmaceutical dosage forms in terms of their physical properties and their chemical composition.

Mapping amorphous material on a partially crystalline surface: Nanothermal analysis for simultaneous characterisation and imaging of lactose compacts

The use of nanothermal analysis for mapping amorphous and crystalline lactose at a nanoscale is explored. Compressed tablets of amorphous and crystalline lactose (alone and mixed) were prepared and localised thermomechanical analysis (L-TMA) performed using micro- and nanothermal analysis in a addition to single point variable temperature pull-off force measurements. L-TMA was shown to be able to identify the different materials at a nanoscale via measurement of the thermal events associated with the amorphous and crystalline regions, while pull off force measurements showed that the adhesion of the amorphous material increased on approaching the T(g). Imaging was performed isothermally using topographic and pulsed force mode (PFM) measurements; both approaches were capable of discriminating two regions which L-TMA conformed to correspond to the two materials. In addition, force volume imaging (FVI) is suggested as a further approach to mapping the surfaces. We demonstrate that performing heated tip PFM measurements at a temperature close to the T(g) allows greater discrimination between the two regions. We therefore suggest that the nanothermal approach allows both characterisation and imaging of partially amorphous surfaces, and also demonstrate that heated tip imaging allows greater discrimination between crystalline and amorphous materials than is possible using ambient studies.

An Investigation into the Surface Deposition of Progesterone on Poly (d,l-) Lactic Acid Microspheres Using Micro-Thermal Analysis

Polylactic acid microspheres are well established as delivery vehicles for a range of low molecular weight and proteinaceous drugs (1–3). However, there is arguably a paucity of information available regarding the physical characteristics of these spheres, with few studies (4) addressing the issue of the manner in which drugs are distributed through the polymeric matrix. Following earlier studies (5,6) we recently investigated the use of modulated temperature DSC (MTDSC) as a means of monitoring the distribution of progesterone within poly(d,l-lactide) spheres using a range of loadings up to 50% w/w (7). By monitoring the thermal response of the spheres we obtained strong evidence for the drug being present as a separate amorphous phase at 30% w/w loading and as a distinct crystalline phase at 50% w/w loading. Complementary SEM studies showed marked changes in the surface morphology of the spheres at these two concentrations, leading to the suggestion of surface drug deposition. However, it was not possible at that stage to definitively establish the location of the drug using the methodologies available. A recent advance within the thermal analysis field has been the introduction of micro-thermal analysis (micro-TA, 8–10). This method is based on the same principles as conventional AFM but involves the replacement of the probe tip with a Wollaston wire loop. The apex of the wire is etched away to leave the silver filament exposed, resulting in a higher resistance in this section of the tip. Application of a voltage therefore results in Joule heating, hence one may apply a thermal signal to highly specific regions of a sample. In addition, the technique allows isothermal measurement of thermal conductivity by rastering over the surface and measuring the tip resistance. The technique has attracted considerable interest, particularly within the polymer science field, as it represents a unique method of performing thermal analysis on highly specific regions of a sample without the necessity of heating the material in its entirety. Early studies on pharmaceutical materials have also yielded highly encouraging results (11,12). The ability of micro-TA to perform localised thermal analysis suggests that the method may be a means of establishing whether the progesterone is indeed present on the surface of the aforementioned microspheres. The objective of the present study was therefore to investigate the use of micro-TA as a novel means of characterising the surface of the PLA microspheres, with a particular view to obtaining further evidence for the presence or absence of progesterone on the exterior of the spheres.

Application of Calorimetry, Sub-Ambient Atomic Force Microscopy and Dynamic Mechanical Analysis to the Study of Frozen Aqueous Trehalose Solutions

PurposeDisaccharides such as trehalose are widely used as cryo-protectants to maintain the activity of proteinaceous drugs during freezing. One unresolved issue is the double transition that is observed very commonly in DSC experiments on disaccharide solutions in the frozen state; the assignment of these transitions remains disputed. Here we use calorimetry and two new techniques to shed light on the true nature of these transitions.MethodsModulated Temperature DSC (MTDSC), cryo atomic force microscopy (AFM) and a novel DMA technique were used to study these transitions.ResultsMTDSC identified the two transitions Tr1 and Tr2 at −35.4 and −27.9°C respectively in the reversing heat flow signal, an exotherm and endotherm were observed in the non-reversing signal at circa −32 and −29°C respectively. It is shown for the first time that AFM images can be obtained of a softening and melting sample without damaging it. A force modulation imaging technique showed a softening at Tr1 and a loss of ice crystals at Tr2. These observations were supported by the DMA results.ConclusionsThe results indicate Tr1 is associated with a glass transition while Tr2 is associated with the onset of loss of crystallinity.

Thermal Probe Based Analytical Microscopy: Thermal Analysis and Photothermal Fourier-Transform Infrared Microspectroscopy Together with Thermally Assisted Nanosampling Coupled with Capillary Electrophoresis

In this study, we have demonstrated that a scanning probe microscope (SPM) can be used for thermally assisted nanosampling (TAN) with subsequent analysis by capillary electrophoresis (CE). Localized thermomechanical analysis (L-TMA) and photothermal Fourier-transform infrared (PT-FTIR) microspectroscopy can also be employed using the same probe, thus illustrating how a single instrument can carry out a number of different complementary analytical measurements. Benzoic acid and 4-hydroxybenzoic acid were manipulated with a heated Wollaston wire probe and successfully deposited onto the surface of a piece of CE capillary tubing. The deposited samples were then separated with CE. L-TMA and PT-FTIR were also used to characterize these materials. We have also demonstrated how a nanosample of a nonparticulate material can be taken and then deposited onto the surface of an inert matrix. TAN of a nonparticulate material was explored using polyethylene as the analyte and fluorene as the matrix. These examples show that thermal probe techniques provide a versatile tool box of modes of analysis with the potential to analyze a wide range of samples in a spatially resolved way.