Joseph F. Krzyzaniak

Lysis of human red blood cells 2: effect of contact time on cosolvent induced hemolysis

Abstract The degree of hemolysis induced by several cosolvent formulations is evaluated at various contact times using the dynamic in vitro method developed by Krzyzaniak (Krzyzanik, J.F., Raymond, D.M. and Yalkowsky, S.H., Lysis of Human Red Blood Cells 1: Effect of Contact Time on Water Induced Hemolysis. PDA J. Pharm. Sci. & Tech., 50 (1996) 223–226). Hemolysis is shown to increase with cosolvent concentration and to be sigmoidally related to the logarithm of the formulation:blood contact time. With this information, a physiologically realistic in vitro method with a formulation:blood ratio of 0.1 and a contact time of 1 s has been developed and used to estimate the amount of hemolysis occurring after an intravenous injection of some commonly used cosolvent formulations.

Use of in situ atomic force microscopy to follow phase changes at crystal surfaces in real time.

AFM of cocrystals: Atomic force microscopy can be used to observe phase changes at crystal surfaces where the transformation is accompanied by a change in the spacing between layers of molecules. The conversion of a metastable polymorph of the caffeine-glutaric acid cocrystal into the thermodynamically stable form was analyzed continuously in situ using intermittent-contact-mode atomic force microscopy.

Mechanism and Kinetics of Punch Sticking of Pharmaceuticals

Adherence of powder onto tablet tooling, known as punch sticking, is one of the tablet manufacturing problems that need to be resolved. An important step toward the resolution of this problem is to quantify sticking propensity of different active pharmaceutical ingredients (APIs) and understand physicochemical factors that influence sticking propensity. In this study, mass of adhered material onto a removable upper punch tip as a function of number of compression is used to monitor sticking kinetics of 24 chemically diverse compounds. We have identified a mathematical model suitable for describing punch sticking kinetics of a wide range of compounds. Chemical analyses have revealed significant enrichment of API content in the adhered mass. Based on this large set of data, we have successfully developed a new punch sticking model based on a consideration of the interplay of interaction strength among API, excipient, and punch surface. The model correctly describes the general shape of sticking profile, that is, initial rise in accumulated mass followed by gradual increase to a plateau. It also explains why sometimes sticking is arrested after monolayer coverage of punch surface by API (punch filming), while in other cases, API buildup is observed beyond monolayer coverage.

Powder properties and compaction parameters that influence punch sticking propensity of pharmaceuticals

Punch sticking is a frequently occurring problem that challenges successful tablet manufacturing. A mechanistic understanding of the punch sticking phenomenon facilitates the design of effective strategies to solve punch sticking problems of a drug. The first step in this effort is to identify process parameters and particle properties that can profoundly affect sticking performance. This work was aimed at elucidating the key material properties and compaction parameters that influence punch sticking by statistically analyzing punch sticking data of 24 chemically diverse compounds obtained using a set of tooling with removable upper punch tip. Partial least square (PLS) analysis of the data revealed that particle surface area and tablet tensile strength are the most significant factors attributed to punch sticking. Die-wall pressure, ejection force, and take-off force also correlate with sticking, but to a lesser extent.

Crystalline mesophases: Structure, mobility, and pharmaceutical properties.

Crystalline mesophases, which are commonly classified according to their translational, orientational, and conformational order as liquid crystals, plastic crystals, and conformationally disordered crystals, represent a common state of condensed matter. As an intermediate state between crystalline and amorphous materials, crystalline mesophases resemble amorphous materials in relation to their molecular mobility, with the glass transition being their common property, and at the same time possessing a certain degree of translational periodicity (with the exception of nematic phase), with corresponding narrow peaks in X-ray diffraction patterns. For example, plastic crystals, which can be formed both by near-spherical molecules and molecules of lower symmetry, such as planar or chain molecules, can have both extremely sharp X-ray diffraction lines and exhibit glass transition. Fundamentals of structural arrangements in mesophases are compared with several types of disorder in crystalline materials, as well as with short-range ordering in amorphous solids. Main features of the molecular mobility in crystalline mesophases are found to be generally similar to amorphous materials, although some important differences do exist, depending on a particular type of mobility modes involved in relaxation processes. In several case studies reviewed, chemical stability appears to follow the extent of disorder, with the stability of crystalline mesophase found to be intermediate between amorphous (least stable) and crystalline (most stable) materials. Finally, detection of crystalline mesophases during manufacturing of two different types of dosage forms is discussed.

Thermodynamic stability considerations for isostructural dehydrates.

Nonstoichiometric channel hydrates are a class of crystalline hydrates that can incorporate a range of water levels as a function of temperature and relative humidity (RH). When a nonstoichiometric channel hydrate can dehydrate to yield a physically stable isostructural crystalline lattice, it may become challenging to accurately evaluate the thermodynamic stability relationship associated with a polymorphic system using traditional methods. This work demonstrates application of a eutectic-melting method to determine the stability relationship between a nonstoichiometric channel dehydrate and an anhydrous form. A transition temperature (122°C) between the isostructural dehydrate of the nonstoichiometric channel hydrate and the anhydrous polymorph was identified, with the nonstoichiometric channel hydrate being the thermodynamically stable anhydrous form at room temperature (RT). Solid-state storage at a range of RH conditions demonstrated that the nonstoichiometric channel hydrate is also the stable form at RT above an RH of 94%. These results demonstrate that the nonstoichiometric channel hydrate is the stable form at low temperatures, independent of its hydration state. It has been demonstrated that the eutectic-melting method is applicable to the study of thermodynamic stability relationships between anhydrous forms and dehydrated channel hydrates.

Dependence of Punch Sticking on Compaction Pressure—Roles of Particle Deformability and Tablet Tensile Strength

Punch sticking is a complex phenomenon influenced primarily by particle size, tooling surface roughness, tooling design, and tooling construction material. When particle and environmental factors are controlled, compaction pressure has a distinct effect on punch sticking behavior for a given active pharmaceutical ingredient (API). This research focuses on the effect of compaction pressure on punch sticking using 5 compounds with different sticking propensities. The results collectively show that sticking tends to be more problematic under higher compaction pressures and for more ductile compounds. This is attributed to the greater punch surface coverage by the API and the stronger cohesion of API to the existing API layer on the punch.

Varenicline L-tartrate Crystal Forms: Characterization Through Crystallography, Spectroscopy, and Thermodynamics

This research utilized crystallographic, spectroscopic, and thermal analysis data to assess the thermodynamic stability relationship between the three known crystal forms of Varenicline L-tartrate. Of the two anhydrous forms (Forms A and B), Form B was determined to be the stable form at 0 K based on its calculated true density, hydrogen bonding in the crystal lattice, and application of the IR rule. Form A has a higher melting point and higher solubility at room temperature as compared to Form B, indicating that these forms are enantiotropically related. Application of the eutectic-melting method enabled accurate determination of the transition temperature (63 degrees C), with Form B as the stable anhydrous form at room temperature. The stability relationships between the anhydrous polymorphs and the monohydrate (Form C) were assessed through exposure of the anhydrous forms to a range of water vapor pressures at room temperature. A phase boundary was identified, with the monohydrate being the thermodynamically stable form above critical water activity values of 0.85 and 0.94 for Forms A and B, respectively. These results provide a better understanding of the form stability as it relates to normal manufacturing and storage conditions for the active pharmaceutical ingredient and drug product.

Crystalline, liquid crystalline, and isotropic phases of sodium deoxycholate in water

Sodium deoxycholate (NaDC) is an important example of bile salts, representing systems with complex phase behavior involving both crystalline and mesophase structures. In this study, properties of NaDC-water mixtures were evaluated as a function of composition and temperature via X-ray diffraction with synchrotron (sXRD) and laboratory radiation sources, water sorption, polarized light, hot-stage microscopy, and freezing-point osmometry. Several phases were detected depending on the composition and temperature, including isotropic solution phase, liquid crystalline (LC) phase, crystalline hydrate, and ice. The LC phase was identified as hexagonal structure by sXRD, with up to 14 high-order reflections detected. The crystalline phase was found to be nonstoichiometric hydrate, based on XRD and water sorption data. The phase diagram of NaDC-water system has been refined based on both results of this study and other reports in literature.

Impact of Solid-State Form on the Disproportionation of Miconazole Mesylate

Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A major challenge with the salt form is its tendency to disproportionate to produce the un-ionized API form, decreasing the solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated. In particular, the role of the solid-state properties of the salt on the disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally designing robust pharmaceutical formulations.