Ann W. Newman

Physical Characterization of Pharmaceutical Solids

A general review of the methods available for the physical characterization of pharmaceutical solids is presented. The techniques are classified as being on the molecular level (properties capable of being detected in an ensemble of individual molecules), the particulate level (properties which can be detected through the analysis of an ensemble of particles), and the bulk level (properties which can be measured only using a relatively large amount of material). The molecular-level properties discussed are infrared spectroscopy and nuclear magnetic resonance spectrometry, the particulate-level properties discussed are particle morphology, particle size distribution, powder X-ray diffraction, and thermal methods of analysis, and the bulk-level properties discussed are surface area, porosity and pore size distribution, and powder flow characteristics. Full physical characterization of three modifications of lactose (hydrous, anhydrous, and Fast-Flo) is presented to illustrate the type of information which can be obtained using each of the techniques discussed.

Assessing the performance of amorphous solid dispersions

The characterization and performance of stable amorphous solid dispersion systems were evaluated in 40 research papers reporting active pharmaceutical ingredient (API) dissolution and bioavailability from various systems containing polymers. The results from these studies were broadly placed into three categories: amorphous dispersions that improved bioavailability (∼82% of the cases), amorphous dispersions possessing lower bioavailability than the reference material (∼8% of the cases), and amorphous dispersions demonstrating similar bioavailabilities as the reference material (∼10% of the cases). A comparative analysis of these studies revealed several in vitro and in vivo variables that could have influenced the results. The in vitro factors compared primarily centered on dissolution testing and equipment, content and amount of dissolution media, sink or nonsink conditions, agitation rates, media pH, dissolution characteristics of the polymer, and dispersion particle size. The in vivo factors included reference materials used for bioavailability comparisons, animal species utilized, fasting versus fed conditions, and regional differences in gastrointestinal (GI) content and volume. On the basis of these considerations, a number of recommendations were made on issues ranging from the assessment of physical stability of API-polymer dispersions to in vivo GI physiological factors that require consideration in the performance evaluation of these systems.

Chemical reactivity in solid-state pharmaceuticals: formulation implications

Solid-state reactions that occur in drug substances and formulations include solid-state phase transformations, dehydration/desolvation, and chemical reactions. Chemical reactivity is the focus of this chapter. Of particular interest are cases where the drug-substance may be unstable or react with excipients in the formulation. Water absorption can enhance molecular mobility of solids and lead to solid-state reactivity. Mobility can be measured using various methods including glass transition (T(g)) measurements, solid-state NMR, and X-ray crystallography. Solid-state reactions of drug substances can include oxidation, cyclization, hydrolysis, and deamidation. Oxidation studies of vitamin A, peptides (DL-Ala-DL-Met, N-formyl-Met-Leu-Phe methyl ester, and Met-enkaphalin acetate salt), and steroids (hydrocortisone and prednisolone derivatives) are discussed. Cyclization reactions of crystalline and amorphous angiotensin-converting enzyme (ACE) inhibitors (spirapril hydrochloride, quinapril hydrochloride, and moexipril) are presented which investigate mobility and chemical reactivity. Examples of drug-excipient interactions, such as transacylation, the Maillard browning reaction, and acid base reactions are discussed for a variety of compounds including aspirin, fluoxitine, and ibuprofen. Once solid-state reactions are understood in a pharmaceutical system, the necessary steps can be taken to prevent reactivity and improve the stability of drug substances and products.

An integrated approach to the selection of optimal salt form for a new drug candidate

Abstract A general method was developed to select the optimal salt form for BMS-180431, a novel HMG-CoA reductase inhibitor and a candidate for oral dosage form development, in an expeditious manner at the onset of the drug development process. The physicochemical properties such as hygroscopicity, physical stability of crystal forms at different humidity conditions, aqueous solubility, and chemical stability of seven salts e.g., sodium, potassium, calcium, zinc, magnesium, arginine and lysine, were studied using a multi-tier approach. The progression of studies among different tiers was such that the least time-consuming experiments were conducted earlier, thus saving time and effort. A ‘go/no go’ decision was made after each tier of testing the salts, thus avoiding generation of extensive data on all available salt forms. The hygroscopicities of all BMS-180431 salts were evaluated at tier 1 and four salts (sodium, potassium, calcium and zinc) were dropped from consideration due to excessive moisture uptake within the expected humidity range of pharmaceutical manufacturing plants (30–50% R.H. at ambient temperature). The remaining three salts were subjected to the tier 2 evaluation for any change in their crystal structures with respect to humidity and the determination of their aqueous solubilities in the gastrointestinal pH range. The magnesium salt was dropped from further consideration due to humidity-dependent changes in its crystal structure and low solubility in water (3.7 mg/ml at room temperature). Arginine and lysine salts, which were resistant to any change in their crystalline structures under extremes of humidity conditions (6 and 75% R.H.) and had high aqueous solubilities (> 200 mg/ml), were elevated to tier 3 for the determination of their chemical stability. Based on solid state stability of these two salts under accelerated conditions (temperature, humidity, and presence of excipients), consideration of ease of synthesis, ease of analysis, potential impurities, etc., and input from the marketing group with respect to its preference of counter ion species, the arginine salt was selected for further development. The number of tiers necessary to reach a decision on the optimal salt form of a compound may depend on the physicochemical properties studied and the number of salts available. This salt selection process can be completed within 4–6 weeks and be easily adopted in the drug development program.

Characterization of amorphous API:Polymer mixtures using X-ray powder diffraction

Recognizing limitations with the standard method of determining whether an amorphous API-polymer mixture is miscible based on the number of glass transition temperatures (T(g)) using differential scanning calorimetry (DSC) measurements, we have developed an X-ray powder diffraction (XRPD) method coupled with computation of pair distribution functions (PDF), to more fully assess miscibility in such systems. The mixtures chosen were: dextran-poly(vinylpyrrolidone) (PVP) and trehalose-dextran, both prepared by lyophilization; and indomethacin-PVP, prepared by evaporation from organic solvent. Immiscibility is detected when the PDF profiles of each individual component taken in proportion to their compositions in the mixture agree with the PDF of the mixture, indicating phase separation into independent amorphous phases. A lack of agreement of the PDF profiles indicates that the mixture with a unique PDF is miscible. In agreement with DSC measurements that detected two independent T(g) values for the dextran-PVP mixture, the PDF profiles of the mixture matched very well indicating a phase separated system. From the PDF analysis, indomethacin-PVP was shown to be completely miscible in agreement with the single T(g) value measured for the mixture. In the case of the trehalose-dextran mixture, where only one T(g) value was detected, however, PDF analysis clearly revealed phase separation. Since DSC can not detect two T(g) values when phase separation produces amorphous domains with sizes less than approximately 30 nm, it is concluded that the trehalose-dextran system is a phase separated mixture with a structure equivalent to a solid nanosuspension having nanosize domains. Such systems would be expected to have properties intermediate to those observed for miscible and macroscopically phase separated amorphous dispersions. However, since phase separation has occurred, the solid nanosuspensions would be expected to exhibit a greater tendency for physical instability under a given stress, that is, crystallization, than would a miscible system.

A solid‐state approach to enable early development compounds: Selection and animal bioavailability studies of an itraconazole amorphous solid dispersion

A solid-state approach to enable compounds in preclinical development is used by identifying an amorphous solid dispersion in a simple formulation to increase bioavailability. Itraconazole (ITZ) was chosen as a model crystalline compound displaying poor aqueous solubility and low bioavailability. Solid dispersions were prepared with different polymers (PVP K-12, K29/32, K90; PVP VA S-630; HPMC-P 55; and HPMC-AS HG) at varied concentrations (1:5, 1:2, 2:1, 5:1 by weight) using two preparation methods (evaporation and freeze drying). Physical characterization and stability data were collected to examine recommended storage, handling, and manufacturing conditions. Based on generated data, a 1:2 (w/w) ITZ/HPMC-P dispersion was selected for further characterization, testing, and scale-up. Thermal data and computational analysis suggest that it is a possible solid nanosuspension. The dispersion was successfully scaled using spray drying, with the materials exhibiting similar physical properties as the screening samples. A simple formulation of 1:2 (w/w) ITZ/HPMC-P dispersion in a capsule was compared to crystalline ITZ in a capsule in a dog bioavailability study, with the dispersion being significantly more bioavailable. This study demonstrated the utility of using an amorphous solid form with desirable physical properties to significantly improve bioavailability and provides a viable strategy for evaluating early drug candidates.

Quantitation of cefepime : 2HCl dihydrate in cefepime.2HCl monohydrate by diffuse reflectance IR and powder X-ray diffraction techniques

The identification, characterization and quantitation of crystal forms is becoming increasingly important within the pharmaceutical industry. Multi-disciplinary, physical analytical techniques are necessary for this task. In this work, diffuse reflectance mid-infrared (IR) and powder X-ray diffraction (XRD) analyses were used to identify two different hydrated forms of cefepime.2HCl, a cephalosporin. Characterization of the mono- and dihydrate forms led to separate IR and XRD quantitative assays for the determination of dihydrate content in cefepime.2HCl monohydrate bulk material. For the IR assay, a working range of 1.0-8% (w/w) was established with a minimum quantifiable level (MQL) of 1.0% (w/w) and a limit of detection (LD) of 0.3% (w/w) dihydrate in monohydrate material. The XRD assay displayed a working range of 2.5-15% (w/w) with an MQL of 2.5% (w/w) and an LD of 0.75% (w/w). Cross validation was performed between the two techniques, with a good correlation displayed for each assay as compared with the known concentrations and as compared with each other. In addition, a full evaluation of potential assay errors was made.

The effect of size and mass on the film thickness of beads coated in fluidized bed equipment

Abstract The relationship between the film thickness on a bead, and the beads size and mass in a polydispersed system was studied. Beads with a size distribution in the no. 14–20 mesh range were coated using Glatt fluidized bed units equipped with a Wurster insert. The coated beads were separated into narrower size fractions and dissolution testing of each fraction was performed using the USP basket method. The larger beads exhibited much slower release rates compared to the smaller beads, and the differences could not be explained by the relative surface areas. Examination of the beads by scanning electron microscope indicated that the larger or heavier beads received a thicker film compared to the smaller or lighter beads. This trend was attributed to differences in the fluidization patterns and velocities of the various sized beads.

Physical interactions of magnesium stearate with starch-derived disintegrants and their effects on capsule and tablet dissolution

Abstract Overmixing of magnesium stearate with granules in the hopper of a capsule filling machine can slow down their dissolution because of coating by magnesium stearate, which acts as a water repellant. This phenomenon was systematically investigated using three active ingredients representing a wide range of solubility in 0.1 N hydrochloric acid, the dissolution medium. The active ingredients were hydrochlorothiazide, an antiviral agent SQ32756 (BV-araU), and aztreonam, with solubilities in 0.1 N hydrochloric acid of 0.6, 5.0 and 12 mg/ml, respectively, at 37°C. When capsules of an aqueous wet granulated formulation containing one of the aforementioned active ingredients, hydrous lactose, pregelatinized starch, microcrystalline cellulose, and 1% w/w magnesium stearate were filled using the MG2 Futura capsule filler, capsules from the latter part of the filling run exhibited significantly slower dissolution compared to those from the beginning. The extent of slowdown in dissolution of the capsules varied depending upon the aqueous solubility of the active ingredient. The slowdown was maximum for hydrochlorothiazide capsules followed by SQ32756 and aztreonam capsules, respectively. Further studies using SQ32756 as the active ingredient indicated that replacement of magnesium stearate in the formulation with other hydrophobic lubricants such as calcium or zinc stearate gave similar results. However, replacement of magnesium stearate with hydrophilic lubricants such as Stear-O-Wet® or sodium stearyl fumarate did not result in a slowing of dissolution. Among the hydrophobic lubricants, magnesium stearate caused the maximum slowdown in dissolution, followed by zinc and calcium stearates, respectively. This observed rank order was correlated to the surface area of these lubricants. Furthermore, optimization of magnesium stearate concentration to 0.25% w/w provided enough lubrication for capsule filling while resulting in a capsule with satisfactory dissolution. Replacement of pregelatinized starch by starch-derived superdisintegrants such as Explotab® or Primojel® also resulted in no slowing of dissolution of capsules, even after overmixing with 1% w/w magnesium stearate. Although the granules overmixed with 1% w/w hydrophobic lubricants exhibited slow down in dissolution when filled into capsules, tablets compressed from these granules dissolved rapidly.

Physical characterization of the polymorphic variations of magnesium stearate and magnesium palmitate hydrate species

The anhydrate, dihydrate, and trihydrate phases of chemically pure magnesium stearate and magnesium palmitate have been prepared and characterized as to their structural characteristics. The magnesium palmitate materials were obtained as significantly larger crystals than were the magnesium stearate materials, and the crystals of the dihydrate phase of either material were found to be the most fully developed. The crystal structures of all materials were judged to be very similar to each other, differing primarily in the magnitude of the long (001) crystal spacing. Thermal analysis studies revealed that the water of hydration contained within the dihydrate phases of either magnesium stearate or magnesium palmitate was more tightly bound than was the water of hydration within the corresponding trihydrate phases. These findings provide further support for the structural picture where the water contained in these lattice structures is present between the intermolecular planes.