Paul G. Royall

An evaluation of the use of modulated temperature DSC as a means of assessing the relaxation behaviour of amorphous lactose.

AbstractPurpose. To evaluate the use of Modulated Temperature DSC(MTDSC) as a means of assessing the relaxation behaviour ofamorphous lactose via measurement of the heat capacity, glasstransition (Tg) and relaxation endotherm. Methods. Samples of amorphous lactose were prepared by freezedrying. MTDSC was conducted using a TA Instruments 2920 MDSCusing a heating rate of 2°C/minute, a modulation amplitude of ±0.3°Cand a period of 60 seconds. Samples were cycled by heating to 140°Cand cooling to a range of annealing temperatures between 80°C and100°C, followed by reheating through the Tg region. Systems werethen recooled to allow for correction of the Tg shift effect. Results. MTDSC enabled separation of the glass transition from therelaxation endotherm, thereby facilitating calculation of the relaxationtime as a function of temperature. The relative merits of using MTDSCfor the assessment of relaxation processes are discussed. In addition,the use of the fictive temperature rather than the experimentally derivedTg is outlined. Conclusions. MTDSC allows assessment of the glass transitiontemperature, the magnitude of the relaxation endotherm and the valueof the heat capacity, thus facilitating calculation of relaxation times.Limitations identified with the approach include the slow scanningspeed, the need for careful choice of experimental parameters and theTg shift effect.

Characterisation and Deposition Studies of Recrystallised Lactose from Binary Mixtures of Ethanol/Butanol for Improved Drug Delivery from Dry Powder Inhalers

Dry powder inhaler formulations comprising commercial lactose–drug blends can show restricted detachment of drug from lactose during aerosolisation, which can lead to poor fine particle fractions (FPFs) which are suboptimal. The aim of the present study was to investigate whether the crystallisation of lactose from different ethanol/butanol co-solvent mixtures could be employed as a method of altering the FPF of salbutamol sulphate from powder blends. Lactose particles were prepared by an anti-solvent recrystallisation process using various ratios of the two solvents. Crystallised lactose or commercial lactose was mixed with salbutamol sulphate and in vitro deposition studies were performed using a multistage liquid impinger. Solid-state characterisation results showed that commercial lactose was primarily composed of the α-anomer whilst the crystallised lactose samples comprised a α/β mixture containing a lower number of moles of water per mole of lactose compared to the commercial lactose. The crystallised lactose particles were also less elongated and more irregular in shape with rougher surfaces. Formulation blends containing crystallised lactose showed better aerosolisation performance and dose uniformity when compared to commercial lactose. The highest FPF of salbutamol sulphate (38.0 ± 2.5%) was obtained for the lactose samples that were crystallised from a mixture of ethanol/butanol (20:60) compared to a FPF of 19.7 ± 1.9% obtained for commercial lactose. Engineered lactose carriers with modified anomer content and physicochemical properties, when compared to the commercial grade, produced formulations which generated a high FPF.

A novel powder sample holder for the determination of glass transition temperatures by DMA

The use of a new sample holder for dynamic mechanical analysis (DMA) as a means to characterise the Tg of powdered hydroxypropyl methyl cellulose (HPMC) has been investigated. A sample holder was constructed consisting of a rectangular stainless steel container and a lid engineered to fit exactly within the walls of the container when clamped within a TA instruments Q800 DMA in dual cantilever configuration. Physical mixtures of HPMC (E4M) and aluminium oxide powders were placed in the holder and subjected to oscillating strains (1 Hz, 10 Hz and 100 Hz) whilst heated at 3 degrees C/min. The storage and loss modulus signals showed a large reduction in the mechanical strength above 150 degrees C which was attributed to a glass transition. Optimal experimental parameters were determined using a design of experiment procedure and by analysing the frequency dependence of Tg in Arrhenius plots. The parameters were a clamping pressure of 62 kPa, a mass ratio of 0.2 HPMC in aluminium oxide, and a loading mass of either 120 mg or 180 mg. At 1 Hz, a Tg of 177+/-1.2 degrees C (n=6) for powdered HPMC was obtained. In conclusion, the new powder holder was capable of measuring the Tg of pharmaceutical powders and a simple optimization protocol was established, useful in further applications of the DMA powder holder.

Differences in physical chemistry and dissolution rate of solid particle aerosols from solution pressurised inhalers.

Solution composition alters the dynamics of beclomethasone diproprionate (BDP) particle formation from droplets emitted by pressurised metered dose inhalers (pMDIs). The hypothesis that differences in inhaler solutions result in different solid particle physical chemistry was tested using a suite of complementary calorimetric techniques. The atomisation of BDP-ethanol solutions from commercial HFA-pMDI produced aerodynamically-equivalent solid particle aerosols. However, differences in particle physico-chemistry (morphology and solvate/clathrate formation) were detected by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and supported by hot stage microscopy (HSM). Increasing the ethanol content of the formulation from 8 to 12% (w/w), which retards the evaporation of propellant and slows the increase in droplet surface viscosity, enhanced the likelihood of particles drying with a smooth surface. The dissolution rate of BDP from the 12% (w/w) ethanol formulation-derived particles (63% dissolved over 120 min) was reduced compared to the 8% (w/w) ethanol formulation-derived particles (86% dissolved over 120 min). The addition of 0.01% (w/w) formoterol fumarate or 1.3% (w/w) glycerol to the inhaler solution modified the particles and reduced the BDP dissolution rate further to 34% and 16% dissolved in 120 min, respectively. These data provide evidence that therapeutic aerosols from apparently similar inhaler products, including those with similar aerodynamic performance, may behave non-equivalently after deposition in the lungs.

Infrared Spectroscopy with Heated Attenuated Total Internal Reflectance Enabling Precise Measurement of Thermally Induced Transitions in Complex Biological Polymers

We report an improved tool for acquiring temperature-resolved fourier transform infrared (FT-IR) spectra of complex polymer systems undergoing thermal transitions, illustrated by application to several phenomena related to starch gelatinization that have proved difficult to study by other means. Starch suspensions from several botanical origins were gelatinized using a temperature-controlled attenuated total reflectance (ATR) crystal, with IR spectra collected every 0.25 °C. By following the 995/1022 cm(-1) peak ratio, clear transitions occurring between 59 and 70 °C were observed, for which the midpoints could be determined accurately by sigmoidal fits. The magnitude of the change in peak ratio was found to be strongly correlated to the enthalpy of gelatinization as measured by differential scanning calorimetry (DSC, R(2) = 0.988). An important advantage of the technique, compared to DSC, is that the signal-to-noise ratio is not reduced when measuring very broad transitions. This has the potential to allow more precise determination of the gelatinization parameters of high-amylose starches, for which gelatinization may take place over several tens of °C.

Monitoring crystallisation of drugs from fast-dissolving oral films with isothermal calorimetry

The aim of this study was to evaluate the potential of isothermal calorimetry to monitor and characterize crystallisation in drug-loaded fast-dissolving oral films. Films of polyvinylpyrrolidone (PVP) containing indomethacin were cast into glass ampoules; stability was assessed by monitoring the power changes occurring with time. Three grades of PVP (K10, K25 and K40, where the number multiplied by 1000 gives the average molecular weight) were used. Indomethacin was seen to crystallise from all PVP grades over ca. 24-48 h at two study temperatures (25 and 37 degrees C), as denoted by a large exothermic event. At 25 degrees C the exothermic event was a single peak; at 37 degrees C two peaks were observed. Subsequent analysis of the crystals with differential scanning calorimetry (DSC) and polarized light microscopy determined that the stable gamma-polymorph of indomethacin formed at 25 degrees C while both the gamma- and metastable alpha-polymorphs formed at 37 degrees C. The calorimetric data were converted to relative crystallinity as a function of time and analysed with three crystallisation models (Avrami, Tobin and Urbanovici-Segal) to determine crystallisation kinetics. Of the three models applied the Urbanovici-Segal model best described the data, although this may be because this model contains a term that effectively accounts for deviation from the Avrami model. The rate constants determined were broadly consistent irrespective of the model used. Increasing polymer molecular weight did not generally affect the crystallisation rate, although an increase in temperature did result in a concomitant increase in crystallisation rate. The data suggest that isothermal calorimetry is able to monitor drug crystallisation in polymer films and therefore the technique could be a useful tool for conducting stability assays for fast-dissolving oral medicines.

Application of Solution Calorimetry in Pharmaceutical and Biopharmaceutical Research

In solution calorimetry the heat of solution (Delta(sol)H) is recorded as a solute (usually a solid) dissolves in an excess of solvent. Such measurements are valuable during all the phases of pharmaceutical formulation and the number of applications of the technique is growing. For instance, solution calorimetry is extremely useful during preformulation for the detection and quantification of polymorphs, degrees of crystallinity and percent amorphous content; knowledge of all of these parameters is essential in order to exert control over the manufacture and subsequent performance of a solid pharmaceutical. Careful experimental design and data interpretation also allows the measurement of the enthalpy of transfer (Delta(trans)H) of a solute between two phases. Because solution calorimetry does not require optically transparent solutions, and can be used to study cloudy or turbid solutions or suspensions directly, measurement of Delta(trans)H affords the opportunity to study the partitioning of drugs into, and across, biological membranes. It also allows the in-situ study of cellular systems. Furthermore, novel experimental methodologies have led to the increasing use of solution calorimetry to study a wider range of phenomena, such as the precipitation of drugs from supersaturated solutions or the formation of liposomes from phospholipid films. It is the purpose of this review to discuss some of these applications, in the context of pharmaceutical formulation and preformulation, and highlight some of the potential future areas where solution calorimetry might find applications.

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.

The use of micro-thermal analysis as a means of in situ characterisation of a pharmaceutical tablet coat

The technique of micro-thermal analysis (MTA) has been applied to a commercial sugar coated ibuprofen tablet in order to identify the ability of the method to differentiate between the coat and the tablet core and to characterise the thermal properties of both components using localised thermal analysis. Thermal conductivity measurements in conjunction with intensity histogram analysis indicated that differentiation across the coat/core interface was possible, with a bimodal distribution of pixel intensities corresponding to thermal conductivity noted. Localised thermal analysis studies indicated that the bulk response was dominated by the incorporated ibuprofen, with a discontinuity seen at ca. 70–80°C, corresponding to the published melting point of the drug. The coat showed a discontinuity at ca. 220°C that may be reasonably ascribed to the melting process. It was also noted that the coat showed a small discontinuity at a temperature corresponding to the melting of ibuprofen. In summary, the technique was shown to be capable of identifying the core/coat interface using thermal conductivity measurements, while localised thermal analysis experiments enable the operator to perform thermal analysis experiments on the individual components in situ.

Structural and enzyme kinetic studies of retrograded starch: inhibition of α-amylase and consequences for intestinal digestion of starch

Highlights • Amylase catalytic efficiency and starch digestibility decrease as starch retrogrades.• Retrograded starch binds to amylase and inhibits catalytic activity.• Amylase inhibition has important implications for slowly digestible starch design.