Norbert Rasenack

Micron‐Size Drug Particles: Common and Novel Micronization Techniques

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 comminution (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 physicochemical drug powder properties are decisive for the manufacturing of a dosage form and for therapeutic success, the characterization of the particle surface and powder properties plays an important role. This article summarizes common and novel techniques for the production of a drug in small particle size. The properties of the resulting products that are obtained by different techniques are characterized and compared.

Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs.

AbstractPurpose. The purpose of this study was to evaluate a novel in situ micronization method avoiding any milling techniques to produce nano- or microsized drug particles by controlled crystallization to enhance the dissolution rate of poorly water-soluble drugs. Methods. Ibuprofen, itraconazole, and ketoconazole microcrystals were prepared by the association of the previously molecularly dispersed drug using a rapid solvent change process. The drug was precipitated in the presence of stabilizing agents, such as hydrocolloids. The obtained dispersion was spray-dried. Particle size, morphology, dissolution rate, specific surface area, and wettability were analyzed. Physicochemical properties were characterized using differential scanning calorimetry and X-ray diffractometry. Results. The obtained dispersions showed a homogeneous particle size distribution. Drugs are obtained in a mean particle size of approximately 2 μm and below. A high specific surface area was created and in situ stabilized. Different stabilizers showed differences in protecting the precipitated drug from crystal growth. The surface was hydrophilized because of the adsorbed stabilizer. Thus, a drug powder with markedly enhanced dissolution rate was obtained. Conclusions. In situ micronization is a suitable method for the production of micro-sized drugs. This technique can be performed continuously or discontinuously and uses only common technical equipment. Compared to milled products drug properties are optimized as all particle surfaces are naturally grown, the particle size is more uniformly distributed and the powder is less cohesive.

Microcrystals for dissolution rate enhancement of poorly water-soluble drugs

Slight dissolution rates related to poor water-solubility are one of the well-known difficulties to be covered during the development of new drug substances. The poorly water-soluble drug ECU-01, a low molecular enzyme-inhibitor with anti-inflammatory properties for oral administration, shows a poor dissolution rate. This study is intended to enhance the drug dissolution rate by using microcrystals. The common way for micronization is the milling of previously formed larger crystals. However, milling shows several disadvantages as the newly created surfaces are thermodynamically activated due to the high energy input and not naturally grown. In this study microcrystals were not produced using any cutting up techniques, but only by association. Naturally grown microcrystals were prepared by a precipitation method in the presence of stabilizing agents (e.g. gelatin, chitosan, different types of cellulose ethers) followed by spray-drying of the formed dispersion. First the drug was dissolved in acetone and then precipitated by rapid pouring an aqueous solution of the stabilizer into the drug solution. Particularly, cellulose ethers were able to form stable and homogeneous dispersions of microcrystals (mean particle size = 1 microm) showing a tight particle size distribution. By spray-drying, the drug powder was obtained. The dissolution rate is significantly enhanced (common drug: 4% after 20 min/microcrystals 93% after 20 min) due to the large surface, which is hydrophilized by adsorbed stabilizers as shown by the decreased contact angle (65 and 30 degrees, respectively).

Crystal habit and tableting behavior.

The tableting behavior of drugs can be affected by changes in the crystal habit. Different crystal habits of the common analgesic drugs ibuprofen and acetaminophen were prepared. Their tableting behavior was characterized. In the case of ibuprofen, a plate-shaped crystal was compared with the common needle-shaped form. In the case of acetaminophen, plate-shaped and prismatic crystals of two different particle sizes were prepared. The aim was to find a crystal form that is suitable for direct compression with only a low amount of excipients. This requires a substance that forms stable compacts at low punch forces, having a good flowability and only a low tendency to stick to the punches. In order to compare the tableting behavior of different substances, a comparative factor (T-factor) was calculated, based on typical parts of the punch force/displacement-profile and properties of the resulting compact. This method works with low amounts of substance and allows a rapid reproducible determination of the tableting behavior. The method was evaluated by characterizing different typical excipients normally used for the production of tablets.

Ibuprofen crystals with optimized properties

The common analgesic drug ibuprofen shows bad dissolution and tableting behavior due to its hydrophobic structure. Additionally its high cohaesivity results in low flowability. Because of the bad compaction behavior ibuprofen has to be granulated usually before tableting. Another problem in manufacturing is the high tendency for sticking to the punches. A crystal form with optimized properties of ibuprofen was prepared and characterized in this study. Crystallization was carried out using the solvent change technique in the presence of different water-soluble additives. These additives were only present during the crystallization process and removed after precipitation by a washing process. A nearly pure ibuprofen powder was received, as GC-analysis showed. Plate-shaped crystals with increased powder dissolution, increased flowability and good tableting behavior were obtained. All crystals were determined as isomorphic by DSC and X-ray analysis. Thus the improvement of the substance characteristics of ibuprofen is reached by changes in the outer appearance of the crystals and in surface modifications. Due to the fact that ibuprofen molecules can form hydrogen bonds, additives that can interact with these hydrogen bonds during the crystallization process can modify the properties of the resulting crystals.

In-situ-micronization of disodium cromoglycate for pulmonary delivery

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 microm 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, the Cyclohaler, and the FlowCaps-Inhaler as model devices. The fine particle fraction (FPF) (<5 microm) was increased from 7% for the jet-milled drug to approximately 75% for the in-situ-micronized drug when the pure drug powder was dispersed without any device. Delivery of the engineered particles via the Spinhaler, the FlowCaps-Inhaler and the Cyclohaler increased the FPF from 11 to 46%, 19 to 51%, and 8 to 40%, respectively.

In vitro characterization of jet-milled and in-situ-micronized fluticasone-17-propionate

Particle properties are decisive for therapeutic efficiency of an inhaled pulmonary drug. Jet-milling as the common way for micronization of inhaled powder drugs shows several disadvantages such as a non-homogeneous particle size distribution and unnatural, thermodynamically-activated particle surfaces causing a high agglomeration behavior. For pulmonary use in a dry powder inhaler (DPI) beside a small particle size, a good de-agglomeration activity is required. In this study, fluticasone-17-propionate (FP) is in-situ prepared in a respirable particle size by a controlled crystallization technique. First, the drug is dissolved in acetone and precipitated by a solvent change method in the presence of a cellulose ether (HPMC) as stabilizing hydrocolloid. By rapidly pouring the drug solution into the polymer-rich water phase, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth simultaneously by the presence of the hydrophilic polymer. This dispersion was then spray-dried. The mean particle size of the drug was around 2 microm and consequently in the respirable range. The physico-chemical properties of the in-situ-micronized drug were compared to those of an unmilled and a jet-milled quality. Differences in the X-ray patterns and amorphous parts could be detected for the jet-milled but not for the in-situ-micronized drug. In addition, the aerodynamic behavior of the engineered and the jet-milled FP was analyzed using the FlowCaps inhaler as delivery device and compared to the commercial product Flutide Diskus. The fine particle fraction (FPF) (<5 microm) was increased four-fold from approximately 9% for the jet-milled drug to approximately 40% for the in-situ-micronized drug when the pure drug powder was dispersed with the FlowCaps device.

Simplified formulations with high drug loads for continuous twin-screw granulation.

As different batches of the same excipients will be intermixed during continuous processes, the traceability of batches is complicated. Simplified formulations may help to reduce problems related to batch intermixing and traceability. Twin-screw granulation with subsequent tableting was used to produce granules and tablets, containing drug, disintegrant and binder (binary and ternary mixtures), only. Drug loads up to 90% were achieved and five different disintegrants were screened for keeping their disintegration suitability after wetting. Granule size distributions were consistently mono-modal and narrow. Granule strength reached higher values, using ternary mixtures. Tablets containing croscarmellose-Na as disintegrant displayed tensile strengths up to 3.1MPa and disintegration times from 400 to 466s, resulting in the most robust disintegrant. Dissolution was overall complete and above 96% within 30 min. Na-starch glycolate offers tensile strengths up to 2.8MPa at disintegration times from 25s to 1031s, providing the broadest application window, as it corresponds in some parts to different definitions of orodispersible tablets. Tablets containing micronized crospovidone are not suitable for immediate release, but showed possibilities to produce highly drug loaded, prolonged release tablets. Tablets and granules from simplified formulations offer great opportunities to improve continuous processes, present performances comparable to more complicated formulations and are able to correspond to requirements of the authorities.

Granule size distributions after twin-screw granulation – Do not forget the feeding systems

The aim of this study was to investigate the influence of qualitatively different powder feeder performances on resulting granule size distributions after twin-screw granulation of a highly drug loaded, hydrophobic mixture and a mannitol powder. It was shown that powder feeder related problems usually cannot be identified by trusting in the values given by the feeder. Therefore, a newly developed model for the evaluation of the performance of powder feeders was introduced and it was tried to connect this model to residence time distributions in twin-screw granulation processes. The influence of feeder performances on resulting granule size distributions varied, depending on the applied screw configuration and the used powder. Regarding the hydrophobic and highly drug loaded formulation, which was granulated at an L/S-ratio of 0.5, a pure conveying screw and a medium kneading configuration, consisting of 60° kneading blocks were negatively influenced by poor feeder settings. For optimal settings more narrow distributions could be obtained. For an extensive kneading configuration good and poor settings resulted in mono-modal granule size distributions but were differing in the overall size. Mannitol, a model substance for a liquid sensitive formulation was granulated at an L/S-ratio of 0.075. It was even more important to maintain optimal feeding as mannitol was highly affected by poor feeder performances. Even an extensive kneading configuration could not level the errors in powder feeder performance, resulting in qualitatively different granule size distributions. The results of this study demonstrate the importance of detailed knowledge about applied feeding systems to gain optimal performance in twin-screw granulation.

Continuous Processing of Active Pharmaceutical Ingredients Suspensions via Dynamic Cross-Flow Filtration

Over the last years, continuous manufacturing has created significant interest in the pharmaceutical industry. Continuous filtration at low flow rates and high solid loadings poses, however, a significant challenge. A commercially available, continuously operating, dynamic cross-flow filtration device (CFF) is tested and characterized. It is shown that the CFF is a highly suitable technology for continuous filtration. For all tested model active pharmaceutical ingredients, a material-specific strictly linear relationship between feed and permeate rate is identified. Moreover, for each tested substance, a constant concentration factor is reached. A one-parameter model based on a linear equation is suitable to fully describe the CFF filtration performance. This rather unexpected finding and the concentration polarization layer buildup is analyzed and a basic model to describe the observed filtration behavior is developed.