Monday, May 25, 2009

Quality Dry Powder Formulations for Inhalation

Scanning electron micrographs of salmeterol xinafoate (SX) microparticles: SX crystallized rapidly from PEG 400 (A); SX crystallized slowly from PEG 400 (B); SX crystallized from PEG 6,000 (C); and commercial micronized SX (D).Direct crystallization of active pharmaceutical ingredient (API) particles in the inhalable size range of 1-6 µm may overcome surface energization resulting from micronization. The aerosolization of fluticasone propionate (FP) and salmeterol xinafoate (SX) microcrystals produced by aqueous crystallization from poly(ethylene glycol) solutions was investigated using a twin-stage impinger following blending with lactose.

Fine particle fractions from SX formulations ranged from 15.98 ± 2.20% from SX crystallized from PEG 6000 to 26.26 ± 1.51% for SX crystallized from PEG 400. The FPF of microcrystal formulations increased as the particle size of microcrystals was increased. The aerosolization of SX from DPI blends was equivalent for the microcrystals and the micronized material. FP microcrystals, which had a needle-like morphology, produced similar FPFs (PEG 400: 17.15 ± 0.68% and PEG 6000: 15.46 ± 0.97%) to micronized FP (mFP; 14.21 ± 0.54). The highest FPF (25.66 ± 1.51%) resulted from the formulation of FP microcrystals with the largest median diameter (FP PEG 400B: 6.14 ± 0.17 µm).

Microcrystallization of SX and FP from PEG solvents offers the potential for improving control of particulate solid-state properties and was shown to represent a viable alternative to micronization for the production of particles for inclusion in dry powder inhalation formulations.

Darragh M, Martin GP, Marriott C. Dry powder formulations for inhalation of fluticasone propionate and salmeterol xinafoate microcrystals. J Pharm Sci. 2009;98:503-515. Correspondence to Gary P. Martin, King’s College London, Drug Delivery Research Group, Pharmaceutical Science Division, at +44-20-7848-4791.


Dynamics and Control of Percutaneous Drug Absorption

Drug concentration (C1) in the stratum corneum as a function of time at various depths (Z2 to interface Z5) for B=0.01.The integration of epidermal turnover into the study of transdermal drug-delivery kinetics is addressed in light of classical control theory. A mathematical representation of the process, which includes Fickian diffusion and advection, was formulated in the frequency domain. This transformation facilitated a detailed analysis of the system dynamics and revealed the intricate relationships among a medicament transient absorption through the skin, the epidermal turnover rate, its physicochemical properties, and the amount of drugs in a reservoir.

The process, represented by transcendental transfer functions, was reduced to a second-order system with dead time by minimizing the squared magnitude of the complex error between the original and simplified models. Clinically relevant parameters, such as the time to reach steady-state flux or drug concentration in the skin layers, are readily available from the low-order models.

The time it takes to deliver a specified dose of drug to a particular depth in the skin is a function of the penetration depth and the diffusion coefficients of the drug molecules in the stratum corneum and the viable epidermis. An optimum administration protocol was developed for the transdermal delivery of chemicals when epidermal turnover is likely to affect their absorption into the systemic circulation.

Simon L, Goyal A. Dynamics and control of percutaneous drug absorption in the presence of epidermal turnover. J Pharm Sci. 2009;98:187-204. Correspondence to Laurent Simon, Otto York Department of Chemical Engineering, New Jersey Institute of Technology, at or (973) 596-5263.


Optimize Scale-up for the Primary Drying Phase

Collapse temperature determined using freeze drying microscopy: (A) onset of partial collapse at -25.3°C; (B) full collapse at -23.0°C.This article describes a procedure to facilitate scale-up for the primary drying phase of lyophilization using a combination of empirical testing and numerical modeling. Freeze dry microscopy is used to determine the temperature at which lyophile collapse occurs. A laboratory scale freeze-dryer equipped with manometric temperature measurement is utilized to characterize the formulation-dependent mass transfer resistance of the lyophile and develop an optimized laboratory scale primary drying phase of the freeze-drying cycle.

Characterization of heat transfer at both lab and pilot scales has been ascertained from data collected during a lyophilization cycle involving surrogate material. Using the empirically derived mass transfer resistance and heat transfer data, a semi-empirical computational heat and mass transfer model originally developed by Mascarenhas et al. (Mascarenhas et al., 1997, Comput Methods Appl Mech Eng 148: 105-124) is demonstrated to provide predictive primary drying data at both the laboratory and pilot scale.

Excellent agreement in both the sublimation interface temperature profiles and the time for completion of primary drying is obtained between the experimental cycles and the numerical model at both the laboratory and pilot scales. Further, the computational model predicts the optimum operational settings of the pilot scale lyophilizer, thus the procedure discussed here offers the potential to both reduce the time necessary to develop commercial freeze-drying cycles by eliminating experimentation and to minimize consumption of valuable pharmacologically active materials during process development.

Kramer T, Kremer DM, Pikal MJ, Petre WJ, Shalaev EY, Gatlin GA. A procedure to optimize scale-up for the primary drying phase of lyophilization. J Pharm Sci. 2009;98:307-318. Correspondence to D.M. Kremer, Parenteral Center of Emphasis, Pfizer Inc., Global Research and Development, Groton/New London Laboratories, at or (919) 990-6202.


Characterization of Moisture-Protective Polymer Coatings

Water uptake behavior of free thin films consisting of different moisture-protective polymers during storage at 75% relative humidity and 22°C (room temperature; n=3): (A) entire observation period and (B) zoom on the first day.The aim of this study was to evaluate the moisture-protective ability of different polymeric coatings. Free films and film-coated tablets (with cores containing freeze-dried garlic powder) were prepared using aqueous solutions/dispersions of hydroxypropyl methylcellulose (HPMC), Opadry AMB (a poly[vinylalcohol]-based formulation) and Eudragit E PO (a poly[methacrylate-methylmethacrylate]).

The water content of the systems upon open storage at 75% relative humidity (RH) and 22°C (room temperature) was followed gravimetrically. Furthermore, polymer powders, free films, and coated tablets were analyzed by differential scanning calorimetry (DSC) and dynamic vapor sorption (DVS). The type of polymer strongly affected the resulting water uptake kinetics of the free films and coated tablets. DSC analysis revealed whether or not significant physical changes occurred in the coatings during storage, and whether the water vapor permeability was water-concentration dependent.

Using DVS analysis the critical glass transition RH of Opadry AMB powder and Opadry AMB-coated tablets at 25°C could be determined: 44.0% and 72.9% RH. Storage below these threshold values significantly reduces water penetration. Thus, DVS and DSC measurements can provide valuable information on the nature of polymers used for moisture protection.

Bley O, Siepmann J, Bodmeier R. Characterization of moisture-protective polymer coatings using differential scanning calorimetry and dynamic vapor sorption. J Pharm Sci. 2009;98:651-664. Correspondence to R. Bodmeier, College of Pharmacy, Freie Universität Berlin, at or +49-30-83850643.


Stability of Rifampicin Liposome Dry Powder Formulations

Cryo-transmission electron microscope image of a liposome suspension.Liposomes were used to encapsulate rifampicin (RIF) as an alternative formulation for delivery to the respiratory tract. Factors affecting the stability of liposomes containing RIF were determined. Four liposome suspensions were prepared, containing different millimole ratios of cholesterol (CH) and soybean L—phosphatidylcholine (SPC) by the chloroform film method, followed by freeze drying.

Cryo-transmission electron microscopy, photon correlation spectroscopy, 2H and 31P solid-state nuclear magnetic resonance were used to characterize the liposome suspensions. Differential scanning calorimetry and X-ray diffraction were used to examine the properties of the powder formulations. The powder was dispersed through an Andersen cascade impactor to evaluate the performance of the aerosolized powder.

The liposomes were a mixture of 200-300 nm unilamellar and multilamellar vesicles. Higher CH content in the liposome formulation resulted in a smaller change in size distribution with time, and higher CH content was associated with an increase in the 2H NMR splitting, indicative of an increase in order of the lipid acyl chains. Furthermore, the SS-NMR results indicated that RIF was located between the acyl chains of the phospholipid bilayer and associated with CH molecules.

Fifty percent encapsulation of RIF was obtained when the lipid content was high (SPC 10 mM: CH 10 mM). Mannitol was found to be a suitable cryoprotectant, which is attributed to its crystallinity, and use of mannitol gave particles with a mass median aerodynamic diameter of less than 5 µm. In terms of chemical stability, RIF in dry powder formulations was considerably more stable when compared to RIF aqueous solutions and RIF liposomal suspensions.

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