Preparation of microcrystals by in situ micronization

2011

Drug powders containing micron-size drug particles are used in several pharmaceutical dosage forms. Many drugs, especially newly developed substances, are poorly water soluble, which limits their oral bioavailability. The dissolution rate can be enhanced by using micronized drugs. Small drug particles are also required in administration forms, which require the drug in micron-size size due to geometric reasons in the organ to be targeted (e.g., drugs for pulmonary use). The common technique for the preparation of micron-size drugs is the mechanical commination (e.g., by crushing, grinding, and milling) of previously formed larger particles. In spite of the widespread use of this technique, the milling process does not represent the ideal way for the production of small particles because drug substance properties and surface properties are altered in a mainly uncontrolled manner. Thus, techniques that prepare the drug directly in the required particle size are of interest. Because ph...

KONA Powder and Particle Journal, 2013

Both the FDA (U.S. Food and Drug Administration) and ICH (International Conference on Harmonisation) have urged the incorporation of Quality by Design (QbD) 1) into the manufacture of pharmaceutical products 2). The performance of many pharmaceutical manufacturing processes and the performance of some pharmaceutical products requires a knowledge of powder properties. Under the principles of QbD it is possible to adjust processes to account for variations in powder properties. These adjustments, in turn , require knowledge of the relation between powder properties and manufacturing performance. This relation between powder properties and performance is often not well understood; thus, the required information is not collected. In this paper, particle-particle and particle-surface interactions are considered to be a source of product variability. As particle size effects are intertwined with particle adhesion effects this topic is also considered. From the discussion below, it can be seen that the surface chemistry of particles can vary due to mechanical treatment, crystallization solvent, and surface contamination. Variations in surface chemistry affect interparticle adhesion and thus may lead to process or product performance changes. Issues concerning the role of interparticle adhesion that are related to tableting and dry powder inhalers are discussed in some detail. It is clear that a deeper understanding of the powder state and the establishment of appropriate analytical tools will be required to fully implement QbD. Improvements in par ticle sizing technologies, improvements powder sampling procedures and measurements of particle surface properties will be required. It is hoped that this paper will stimulate thought on this issue.

International Journal of Pharmaceutics, 2010

The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches. After mechanofusion, both poured and tapped densities for all three model drug powders significantly increased. There were significant improvements in aerosolization behavior from an inhaler device for all model powders after mechanofusion. Such improvements in aerosolization were attributed to the reduction in agglomerate strength caused by decreasing powder intrinsic cohesion via surface modification. The work also indicated that the effect of the coating was dependant on the initial particle properties.

European Journal of Pharmaceutics and Biopharmaceutics, 2003

The purpose of this paper is to investigate the influence of the emulsion composition of the feed liquid on physicochemical characteristics of drug-loaded powders produced by spray-freezing into liquid (SFL) micronization, and to compare the SFL emulsion process to the SFL solution process. Danazol was formulated with polyvinyl alcohol (MW 22,000), poloxamer 407, and polyvinylpyrrolidone K-15 in a 2:1:1:1 weight ratio (40% active pharmaceutical ingredient (API) potency based on dry weight). Emulsions were formulated in ratios up to 20:1:1:1 (87% API potency based on dry weight). Ethyl acetate/water or dichloromethane/water mixtures were used to produce o/w emulsions for SFL micronization, and a tetrahydrofuran/water mixture was used to formulate the feed solutions. Micronized SFL powders were characterized by X-ray diffraction, surface area, scanning and transmission electron microscopy, contact angle and dissolution. Emulsions containing danazol in the internal oil phase and processed by SFL produced micronized powders containing amorphous drug. The surface area increased as drug and excipient concentrations were increased. Surface areas ranged from 8.9 m 2 /g (SFL powder from solution) to 83.1 m 2 /g (SFL powder from emulsion). Danazol contained in micronized SFL powders from emulsion and solution was 100% dissolved in the dissolution media within 2 min, which was significantly faster than the dissolution of non-SFL processed controls investigated (, 50% in 2 min). Micronized SFL powders produced from emulsion had similar dissolution enhancement compared to those produced from solution, but higher quantities could be SFL processed from emulsions. Potencies of up to 87% yielded powders with rapid wetting and dissolution when utilizing feed emulsions instead of solutions. Large-scale SFL product batches were manufactured using lower solvent quantities and higher drug concentrations via emulsion formulations, thus demonstrating the usefulness of the SFL micronization technology in pharmaceutical development. q

European Journal of Pharmaceutics and Biopharmaceutics, 2003

Drug particle properties are critical for the therapeutic efficiency of a drug delivered to the lung. Jet-milling, a commonly used technique for micronization of drugs, has several disadvantages such as a non-homogeneous particle size distribution, and unnatural, thermodynamically activated particle surfaces causing high agglomeration. For pulmonary use in a dry powder inhaler, in addition to a small particle size, good de-agglomeration behaviour is required. In this study disodium cromoglycate is prepared in situ in a respirable particle size by a controlled crystallization technique. First the drug is dissolved in water (4%) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as a stabilizing hydrocolloid. By rapidly pouring isopropyl alcohol into the drug solution in a 1:8 (v/v) ratio, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth in the presence of the hydrophilic polymer. This dispersion was spray-dried. The mean particle size of the drug was around 3.5 mm and consequently was in the respirable range. The in-situ-micronized drug powder was tested for its aerodynamic behaviour and compared with jet-milled drug powder and with commercial products using the Spinhaler w , the Cyclohaler w , and the FlowCaps w-Inhaler as model devices. The fine particle fraction (FPF) (,5 mm) was increased from 7% for the jet-milled drug to approximately 75% for the in-situmicronized drug when the pure drug powder was dispersed without any device. Delivery of the engineered particles via the Spinhaler w , the FlowCaps w-Inhaler and the Cyclohaler w increased the FPF from 11 to 46%, 19 to 51%, and 8 to 40%, respectively.

International journal of pharmaceutics, 2012

A novel method was developed to manufacture amorphous formulations of poorly soluble compounds that cannot be processed with existing methods such as spray drying and melt extrusion. The manufacturing process and the characterization of the resulting amorphous dispersion are presented via examples of two research compounds. The novel process is utilized N,N-dimethylacetamide (DMA) to dissolve the drug and the selected ionic polymer. This solution is then co-precipitated into aqueous medium. The solvent is extracted out by washing and the co-precipitated material is isolated by filtration followed by drying. The dried material is referred to as microprecipitated bulk powder (MBP). The amorphous form prepared using this method not only provides excellent in vitro and in vivo performance but also showed excellent stability. The stabilization of amorphous dispersion is attributed to the high T(g), ionic nature of the polymer that help to stabilize the amorphous form by possible ionic in...

Quality by Design principles has been applied to understand formulation and optimization of nano-crystalline spray-dried powders of poorly soluble drugs. The objectives of this research were to: 1) investigate the effect of wet media milling on nano-crystalline suspensions; 2) investigate the effect of spray-drying process and formulation parameters on nano-crystalline suspensions; 3) understand role of bulking agents during spray or freeze-drying of nano-crystalline suspensions; and 4) investigate the effect of different sized spray-dried nano-crystals on in vitro dissolution performance. Poorly soluble drugs were utilized to investigate the aggregation of nano-crystals during the spray drying process. It was determined that temperature and excipient utilized in the formulations plays an important role in nano-crystal aggregation. Low inlet temperature (preferably less than drug melting temperature) for spray drying processing and the addition of stabilizers/excipients with favorable or strong interaction (such as ionic or hydrogen bonding etc.) with the drug will provide better stability of the nano-crystals and thus no or minimal nano-crystal aggregation. The percent yield of spray-dried powders is dependent on the glass transition temperature of the formulations and/or bulking agents utilized. Small molecular weight bulking agents (or matrix formers) prevented nanocrystal aggregation due to favorable interactions with the stabilizers.

European Journal of Pharmaceutical Sciences, 2004

We formulated cetrorelix acetate, as an adhesive mixture for use in dry powder inhalation. To achieve the highest possible deposition efficiency we investigated both the influence of different micronization techniques and different inhalers. The Novolizer with an air classifier as the powder de-agglomeration principle and the ISF inhaler were used for in vitro deposition experiments (cascade impaction). Micronization by milling as the classical approach and micronization by spray drying and spray freeze drying as advanced particle engineering techniques were investigated to determine whether advanced techniques are necessary to obtain high fine particle fractions (FPF) for this specific drug. It was found that the effects obtained with a certain micronization technique depended on the complex interaction of the physical characteristics of the drug substance with the type of formulation chosen, as well as with the deagglomeration principle used. The combination of particle engineering by spray drying and the use of the air classifier technology resulted in a fine particle fraction of 66%, while spray freeze drying yielded extremely fragile particles resulting in a FPF of only 25%. The behaviour of the milled material showed similar trends as the spray dried material but FPF values were lower. It was concluded that when a drug is to be formulated as a powder for inhalation with high fine particle fractions, it is profitable to use advanced particle engineering techniques, however the applied technique should be tuned with the characteristics of the formulation type and process as well as with device development.

Journal of aerosol …, 2003

Comparative analysis of salmeterol xinafoate (SX) powders was carried out to define the aerodynamic properties and mechanism of particle dispersion relevant to the use of these materials in dry powder inhalation drug delivery. Particle sizing methodology was evaluated using laser diffraction, time-of-flight and Andersen cascade impactor measurements combined with electron microscopy and surface area determination. Particle interactions, assessed on the basis of powder bulk density and inverse gas chromatography surface energy measurements, were compared with the aerodynamic forces generated by a dry-powder dispersion device. The supercritically produced material showed by a factor of seven reduced tensile strength of the aggregates and indicated a two-fold increase of fine particle fraction deposited in a cascade impactor when blended with lactose. This effect was explained by the reduced particle aggregation at low differential air pressures and flow rates. A relatively small value of aerodynamic stress required to disperse supercritically produced particles in comparison to micronized material comes from: (a) lower bulk density (loose aggregate structure), (b) larger volume mean diameter, (c) larger aerodynamic shape factor and (d) smaller specific free energy of S-SX particles, in this order of priority. It is shown that aggregation between primary drug particles is important for SX/lactose formulations because such aggregates survive the pre-separation impactor stage.

Journal of Pharmaceutical Sciences, 1971