Stephen R. Byrn

Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations

AbstractPurpose. This review describes a conceptual approach to the characterization of pharmaceutical solids. Methods. Four flow charts are presented: (1) polymorphs, (2) hydrates, (3) desolvated solvates, and (4) amorphous forms. Results. These flow charts (decision trees) are suggested as tools to develop information on pharmaceutical solids for both scientific and regulatory purposes. Conclusions. It is hoped that this review will lead to a more direct approach to the characterization of pharmaceutical solids and ultimately to faster approval of regulatory documents containing information on pharmaceutical solids.

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.

Physical characteristics and chemical degradation of amorphous quinapril hydrochloride

This study was designed to investigate the relationships between the solid-state chemical instability and physical characteristics of a model drug, quinapril hydrochloride (QHCl), in the amorphous state. Amorphous QHCl samples were prepared by rapid evaporation from dichloromethane solution and by grinding and subsequent heating of the crystalline form. Physical characteristics, including the glass transition temperature and molecular mobility, were determined using differential scanning calorimetry, thermogravimetric analysis, powder x-ray diffractometry, polarizing microscopy, scanning electron microscopy, and infrared spectroscopy. The amorphous form of QHCl, produced by both methods, has a T(g) of 91 degrees C. Isothermal degradation studies showed that cyclization of QHCl occurred at the same rate for amorphous samples prepared by the two methods. The activation energy was determined to be 30 to 35 kcal/mol. The rate of the reaction was shown to be affected by sample weight, dilution through mixing with another solid, and by altering the pressure above the sample. The temperature dependence for chemical reactivity below T(g) correlated very closely with the temperature dependence of molecular mobility. Above T(g), however, the reaction was considerably slower than predicted from molecular mobility. From an analysis of all data, it appears that agglomeration and sintering of particles caused by softening of the solid, particularly above T(g), and a resulting reduction of the particle surface/volume ratio play a major role in affecting the reaction rate by decreasing the rate of removal of the gaseous HCl product.

Glycine Crystallization During Freezing: The Effects of Salt Form, pH, and Ionic Strength

AbstractPurpose. The purpose of the study is to characterize glycine crystallization during freezing of aqueous solutions as a function of the glycine salt form (i.e., neutral glycine, glycine hydrochloride, and sodium glycinate), pH, and ionic strength. Methods. Crystallization was studied by thermal analysis, microscopy, x-ray diffraction, and pulsed Fourier transform nmr spectroscopy. Results. A solution of neutral glycine with no additives undergoes rapid secondary crystallization during freezing, forming the β polymorph, with a eutectic melting temperature of −3.4°C. Glycine hydrochloride solutions undergo secondary crystallization relatively slowly, and the eutectic melting temperature is −28°C. Sodium glycinate crystallizes from frozen solution at an intermediate rate, forming a eutectic mixture with a melting temperature of −17.8°C. Where secondary crystallization does not occur rapidly, a complex glass transition is observed in the −70° to − 85°C temperature range in the DSC thermograms of all systems studied. Rates of secondary crystallization and the type of crystal formed are influenced by solution pH relative the the pKs of glycine, and also by the change in ionic strength caused by adjustment of pH. Increased ionic strength significantly slows the crystallization of neutral glycine and promotes formation of the γ polymorph. Thermal treatment or extended holding times during the freezing process may be necessary in order to promote secondary crystallization and prevent collapse during freeze drying. Conclusions. The results underscore the importance of recognizing that seemingly minor changes in formulation conditions can have profound effects on the physical chemistry of freezing and freeze drying.

Goniothalenol: a novel, bioactive, tetrahydrofurano-2-pyrone from Goniothalamus giganteus (Annonaceae)

Abstract Fractionation of the stem bark of the title plant, monitoring for bioactivity with brine lethality, led to the isolation of goniothalenol (I). Mass, 1HNMR, and 13CNMR spectral data helped to characterized I as a phenyltetrahydrofurano-2-pyrone, as a novel heterocyclic ring system for natural compounds. X-Ray crystallographic analysis confirmed the structure and established the configuration for I.

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.

Solid-state nuclear magnetic resonance (NMR) spectra of pharmaceutical dosage forms

Solid-state 13C NMR spectra of tablets or capsules of prednisolone, enalapril maleate, lovastatin, simvastatin, ibuprofen, flurbiprofen, mefenamic acid, indomethacin, diflunisal, sulindac, and piroxicam were obtained in the CP/MAS mode at 50 MHz. These studies show that (1) solid-state NMR spectroscopy can detect the active ingredients in low-dose tablets and capsules; (2) the use of interrupted decoupling often results in suppression of resonances due to excipients, thereby allowing better detection of resonances from the drug; and (3) the technique permits discrimination between two prednisolone polymorphs present in tablets obtained from various manufacturers even though the tablets contain only approximately 5% (w/w) of the drug.

Advances in pharmaceutical materials and processing

Abstract Advances in pharmaceutical materials and processing require new generations of pharmaceutical technologies, which in turn require an improved understanding of each step in the unit processes of dosage form development. The unit processes range from raw material qualification to final product release using process monitoring of critical steps. The authors illustrate some recent research trends in understanding and improving pharmaceutical materials and processing through the use of experience obtained within several research programs at Purdue University (West Lafayette, IN, USA).

Modeling and Monitoring of Polymorphic Transformations During the Drying Phase of Wet Granulation

AbstractPurpose. The purpose of this work was to monitor polymorphic transformations of glycine during the drying phase of a wet granulation and model the polymorphic conversions using a time-based reconciliation model. Methods. Near-infrared spectroscopy (NIR) was used for quantitation of polymorphs, and X-ray powder diffraction (XRPD) was used for qualitative analysis of polymorphs. Results. The data show that the faster the granulation was dried, the more kinetic trapping of the metastable α-glycine polymorph, as predicted by reconciliation of the time scales of both the drying rate and the rate of the solution-mediated conversion. Conclusions. By knowing basic properties of the drug substance (solubility of the polymorphic forms and the rate of the solution-mediated conversion), processing conditions, such as the drying rate, can be adjusted to anticipate and prevent potential polymorphic transformations.

Additive-Induced Metastable Single Crystal of Mefenamic Acid

PurposeTo utilize additives to develop a strategy and a method to grow single crystals that allow structure determination of a metastable form of a drug.Materials and MethodsThe metastable form of mefenamic acid (MFA) was grown in the presence of various amounts of the structurally similar additive flufenamic acid (FFA) in ethanol. Single crystal X-ray analysis was performed on the single crystals of MFA II that were formed. The solubility of MFA in the presence of FFA was measured to elucidate the mechanism of MFA II formation.ResultsA supersaturated solution of MFA in ethanol produced the metastable form using FFA as an additive. Ethanol–water mixtures and toluene were also used to investigate the relationships between form produced and solvent since these two solvent systems do not produce MFA II.ConclusionsAdditives can be used to obtain the metastable form of pharmaceutical compounds, and the relationships between molecules and solvent as well as between host and guest molecules are critical to obtaining the desired form.