Graham Buckton

The use of isothermal microcalorimetry in the study of changes in crystallinity induced during the processing of powders

Abstract Isothermal microcalorimetry has been used to follow recrystallisation of amorphous regions of powder surfaces. Lactose monohydrate was taken as a model powder, and was processed by spray drying and micronisation. Spray drying produced an amorphous powder (as shown by X-ray diffraction), which was found to recrystallise when exposed to humidities over 50% RH. The recrystallisation process was extremely cooperative, with the entire sample recrystallising almost instantaneously, rather than a gradual process over the period of exposure to the water vapour. Similar results were noted when micronised material was investigated. The amount of amorphous material produced during micronisation was directly proportional to the intensity of the process. It proved possible to quantify the % amorphous content of powder sample with a resolution of at least 1%, which is considerably better than other techniques. The amorphous regions of the lactose crystallised as either α- or β-lactose. The difference between these samples could be detected by X-ray diffraction, and also could be seen by isothermal calorimetry, as the β-regions mutarotated to α-lactose. The application of isothermal microcalorimetry to studies of crystal properties of powders provides a quantitative characterisation of many aspects of crystallinity and crystal transition. The data obtained can subsequently be used to characterise the properties of the material, and to show how and when crystallisation will occur, and to aid predictions of the product of the crystallisation process. The demonstration of these applications provides a huge potetential for the use of isothermal microcalorimetry in this field of study.

The use of gravimetric studies to assess the degree of crystallinity of predominantly crystalline powders

An accurate humidity and temperature controlled microbalance system (dynamic vapour sorption) has been used to investigate the water sorption properties of mixtures of amorphous lactose (spray dried) and crystalline a-lactose monohydrate. From the shape of the sorption isotherms it could be seen that the first sorption process for each sample showed higher weight gain due to absorption into the amorphous regions, than was observed for the subsequent adsorption events on the sample. For the first sorption process, the weight fell after the humidity reached about 60% RH, as the amorphous material recrystallised (causing expulsion of absorbed water). On desorption there was always residual water after the first cycle, which correlated reasonably well with the residual that would be predicted if the amorphous material had been converted into the monohydrate form. The water sorption technique can readily be used to demonstrate the existence of amorphous material even for mixtures which contain as little as 0.05% w/w, and it is possible that the residual weight change may be used as an approximate quantification of the original amorphous content of the sample.

Assessment of disorder in crystalline powders--a review of analytical techniques and their application.

The need to be able to measure amorphous contents in crystalline powders is now recognised. In this review, calorimetric and gravimetric methods are reviewed in a way that should alert workers in the field to the theoretical, and practical considerations which are important to understanding how best to study crystalline samples which contain low levels of amorphous material. It is shown that vapour sorption techniques are very powerful as long as serious consideration is given to the choice of environmental conditions and the exact experimental methodology. As the amount of published work in this field grows, it becomes increasingly necessary to describe experimental and data manipulation methods in great detail.

Characterisation of small changes in the physical properties of powders of significance for dry powder inhaler formulations

In this paper we address the following issue: Why is surface characterisation important? All pharmaceutical processes (with the exception of mixing two gasses) involve interfacial contact, and, consequently, it is not surprising that surface energetics play an important role in determining the outcome of all events. For a dry powder inhaler system interfacial considerations may relate to drug-drug interactions (cohesion), drug-carrier or drug-device interactions (adhesion) and deaggregation phenomena during use. As all adhesive and cohesive interactions are interfacial phenomena it is reasonable to accept that the basis of interactions within dry powder inhalers is through interfacial forces, which can be divided into apolar (Lifshitz-van der Waals) and polar (electron donor-electron acceptor) components. Further to this it can be accepted that changes in the nature of any surface within the product (the drug, the carrier or the container) can be expected to result in changes in the surface interactions involving that phase. Thus, in essence, the success or failure of a formulated inhalation device is dependent upon the nature of the surface of the materials used, and, as such, measurement of these surfaces becomes of paramount importance. In this review comparatively little effort will be taken to prove the dominant role of surface energetics in inhalation products; this is primarily because much of the proof which exists is held as confidential by manufacturers. Consequently, this review will concentrate on surface characterisation of powders with respect to determination of surface energies and changes in solid-state properties.

The Use of Inverse Phase Gas Chromatography to Measure the Surface Energy of Crystalline, Amorphous, and Recently Milled Lactose

AbstractPurpose. To assess differences in surface energy due to processing induced disorder and to understand whether the disorder dominated the surfaces of particles. Methods. Inverse gas chromatography was used to compare the surface energies of crystalline, amorphous, and ball milled lactose. Results. The milling process made ca 1% of the lactose amorphous, however the dispersive contribution to surface energy was 31.2, 37.1, and 41.6 mJ m−2 for crystalline, spray dried and milled lactose, respectively. A physical mixture of crystalline (99%) and amorphous (1%) material had a dispersive surface energy of 31.5 mJ m−2. Conclusion. Milling had made the surface energy similar to that of the amorphous material in a manner that was very different to a physical mixture of the same amorphous content. The milled material will have similar interfacial interactions to the 100% amorphous material.

The use of near infra-red spectroscopy to detect changes in the form of amorphous and crystalline lactose

Abstract The suitability of near infra-red spectroscopy (NIR) to follow changes in both the amorphous and crystalline state of lactose at room temperature was investigated. Amorphous lactose samples were stored in sealed glass jars with saturated salt solutions to control the relative humidity. NIR spectra were recorded after various periods of storage and the data related to calorimetric and thermo-gravimetric assessments of the physical form of the material. Differentiation between crystalline and amorphous states of lactose was found possible by studying the shape and magnitude of regions of the near infra-red spectrum corresponding to combination and first overtone stretching frequencies of water. It was possible to follow changes in the amorphous, the onset of crystallisation and the solid state transition from β - to α -lactose. NIR with benefits of being non-invasive, non-destructive and operating at room temperature, has been shown to be a valuable tool with which to assess changes in the physical form of lactose.

The use of isothermal microcalorimetry in the study of small degrees of amorphous content of a hydrophobic powder

The crystallinity of a hydrophobic drug (L-365,260) has been investigated by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and isothermal microcalorimetry. The crystallinity was assessed in the isothermal microcalorimeter by taking a ratio of the responses seen when an unknown sample and an amorphous standard were exposed to ethanol vapour. It was found that large amounts of the material (up to 75%) became amorphous with protracted micronisation. The XRPD, DSC and isothermal microcalorimetry methods could all be used to characterise the amorphous content for these highly disordered samples. When the drug was milled in a ball mill, considerably less of the sample mass became amorphous (less than 10% even for reasonably long milling times) and for such samples, only isothermal microcalorimetry was a suitable technique for quantifying the degree of disorder as no difference was observed by use of DSC or XRPD for materials with up to 10% amorphous content. Microcalorimetry is a suitable approach for crystallinity studies on hydrophobic powders, giving a lower limit of detection for amorphous content that is in the order of 1% or less, which is well below that seen for XRPD.

The relationship between particle size and solubility

[where the rate of change of mass dissolved (m) with time (t) is related to the diffusion coefficient (D) through a static layer of liquid of thickness h, and C, is the equilibrium solubility and the amount dissolved at time t (C)l * in that an increase in the surface area of a drug will result in a more rapid dissolution process, particularly under sink conditions (where C a C,). This kinetic observation is clear and unambiguous, however, experimental results also lead to the conclusion that the value of C, can be influenced by a change in particle size. For example, Banker and Rhodes (1979) review studies which have shown

Water mobility in amorphous lactose below and close to the glass transition temperature

Abstract The water sorption behaviour of amorphous lactose has been investigated gravimetrically. It was found that the kinetics of absorption at (especially) 40% and (also) 50% RH were bi-phasic. Although we have no explanation for this behaviour, it is noted that the inflection point between the two processes is at a 1:1 mole ratio of water:lactose. Equilibration at 40% RH results in an equilibrium uptake of 7% water, which is not sufficient to lower the Tg of lactose to the temperature of the experiment (T). Following from this, desorption is rapid and the rate proportional to the extent to which the RH has been lowered. If the sample is equilibrated to 50% RH the water content exceeds that which lowers the Tg below Tg this results in a collapse of the amorphous structure, but not in instantaneous recrystallisation. Exposure to higher humidities in an isothermal microcalorimeter revealed that the heat output for recrystallisation of the collapsed amorphous structure was indistinguishable from that produced on recrystallisation of the original expanded amorphous form. The rate of water desorption from the collapsed amorphous structure is slow and follows square root of time dependency. The rate of this diffusion controlled process is not altered by changing the external RH. The duration of exposure to 50% RH alters the extent of collapse, and hence alters the amount of water which is free to leave the sample rapidly and that which is released by the slow diffusion through the solid. After reducing the RH the water content of the collapsed structure remains high, but the recrystallisation is greatly delayed. These studies show that water can be held in different ways within amorphous lactose and this has implications for physical, chemical and potentially even microbiological stability of products.

Assessment of the wettability of powders by use of compressed powder discs

Abstract The value of contact angle measurements on compressed discs of powder has been critically examined as a method of assessing the wettability of five barbiturate powders. The contact angle was found to reduce with increased compression force, until a constant value was achieved. This was demonstrated, by use of scanning electron micrographs, to be due to plastic deformation of the powder surface. The values of θ obtained did not alter after electrostatic forces were discharged with an antistatic gun, and are thus not responsible for the hydrophobic nature of the loosely compressed beds. The effect of drop size, in the range 10 to 50 μl, and surface roughness were not large enough to be detected amongst the scatter of results. Small drops of water on the plane faces of large crystals formed a contact angle in close agreement with the plastic skin on the compacts. It is postulated that the crystal defects and heterogeneities are responsible for raising the value of θ in the uncompacted powders.