Real time PCR - European Pharmaceutical Review

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THERMAL ANALYSIS ISSUE 2009 Calorimetry as a Process Analytical Tool for micronising pharmaceuticals Simon Gaisford, Lecturer in Pharmaceutics, University of London Drug delivery via the pulmonary route is becoming increasingly popular, but brings a unique set of formulation challenges. In particular the small particle sizes (between 2-5 μm) required to facilitate deposition in the lung frequently mean that size-reduction steps (such as milling) are required during processing of constituents (usually the active principal) prior to formulation. Typically either ball mills or air-jet mills are employed to achieve the desired reduction in particle size. In the former case ceramic or metal balls are placed in a container with the sample and whole apparatus is rotated; the size, weight and number of balls can be varied as can the number of revolutions per minute and the total milling time. In the latter case compressed air is used to agitate particles, causing size reduction Figure 1: Particle size distribution as a function of number of micronisation cycles for α-lactose monohydrate (air-jet milled with compressed nitrogen, 50 psi) by particle attrition; the pressure of the air can be varied and centrifugal force determines when the particles are ejected from the mill. On a commercial scale, batches may be milled a number of times to ensure the desired particle size distribution has been achieved. An example (for an air-jet milled sample) is given in Figure 1. Powders with such a small particle size distribution can be difficult to aerosolise; many dry powder inhaler (DPI) formulations thus include a large, coarse substrate (typically lactose) on which the micronised drug is located, bound by a force of adhesion. When the patient inspires, the turbulent air-flow aerosolises the powder blend and then causes deaggregation of the drug and its carrier. The large carrier particles impact the back of the throat and the micronised drug enters the lung. Such an approach is convenient, because the inhaler device is breath actuated and hence the aerosolisation step is coordinated with inspiration 28 www.europeanpharmaceuticalreview.com
SUBSCRIBE ISSUE 2009 THERMAL ANALYSIS (a common problem with pressurised metered dose inhalers (pMDI)). As has been discussed in the literature 1 , the processes involved in particle size reduction during milling are complex. The mechanical forces imparted to a crystalline material during milling result initially in a reduction in particle size, as the material fractures along natural fault lines and crystal defects. Eventually there comes a point at which the bulk material can no longer fracture and maximum particle size reduction has been achieved. Post this point, mechanical forces are still being applied and must be absorbed and dissipated by the sample; these processes result initially in production of surface dislocations and eventually generation of amorphous regions; so called process-induced disorder. As has been well documented elsewhere 2,3 , the amount of amorphous material formed in this way is usually small (of the order of a few percent w/w); however, the nature of the force applied (impaction) means that this amorphous material must necessarily be located on the surface of the milled material and, hence, although the milled material is predominantly crystalline it behaves as if it were entirely amorphous. Newell at al 4 published some inverse phase gas chromatography (IGC) data (see Table 1) that convey this point. It is inevitable that this amorphous material will crystallise, probably over a relatively short timeframe as it is located on a crystalline substrate that can act as a seed. Crystallisation of the surface may have disastrous consequences for the function of the product 5 , primarily because the force of adhesion between drug and carrier will change, altering the balance of forces that is so important in modulating product performance from batch-to-batch and within one batch over time. As such, it is imperative to understand the mechanisms and kinetics of crystallisation, such that its effects can be ameliorated. Often this means conditioning (under humidity or some other suitable plasticising vapour) the material post micronising to force crystallisation. If it is true that particle size reduction occurs before, and not concomitantly with, generation of process induced disorder then it is apparent that it would be possible to micronise a sample without generating any amorphous material. This would remove the need for downstream conditioning and ensure consistent product performance. It is not possible to optimise milling by following particle size reduction alone, since there is no particle sizing technique that can simultaneously detect formation of amorphous content. Returning to the data shown in Figure 1 (page 28), it is tempting to set up a process involving four to five micronising steps, since this seems to ensure a consistent particle size distribution; such an approach does nothing to report the generation of process induced disorder and can lead to the batch-to-batch variability in product performance noted above. Here, we show that following the micronising process with an additional technique, isothermal microcalorimetry, affords extra data that allows optimisation of the micronising time. In addition, the data allow the hypothesis that particle size reduction occurs before the generation of process induced disorder to be tested. Figure 2: Calibration plot of amorphous content versus heat of crystallisation for salbutamol sulphate, determined with IGPC The model drug chosen was salbutamol sulphate (SS), since this is a drug commonly formulated for inhalation. Crystalline SS was prepared by precipitation from acetone while amorphous SS was prepared by spray-drying. Crystalline SS was ball-milled for increasing periods of time; Laser-diffraction particle sizing (Mastersizer, Malvern Instruments Ltd) was used to measure particle size distributions and isothermal gas perfusion calorimetry (IGPC, based in a TAM Table 1: Dispersive surface energy data (recorded with inverse-phase gas chromatography) for various lactose samples [4]. Sample Dispersive surface energy (mJ/m 2 ) Amorphous lactose (spray-dried) 37.1 (2.3) Crystalline lactose monohydrate 31.2 (1.1) Mixture (ca. 1% w/w amorphous) 41.6 (1.4) Milled (ca. 1% w/w amorphous) 31.5 (0.4) GO TO CONTENTS PAGE 29
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