Enabling Efficient Design of Biological Formulations Through Advanced Characterization.

The present review summarizes the use of differential scanning calorimetry (DSC) and scattering techniques in the context of protein formulation design and characterization. The scattering techniques include wide angle X-ray diffractometry (XRD), small-angle neutron scattering (SANS) and small-angle X-ray scattering (SAXS). While DSC is valuable for understanding thermal behavior of the excipients, XRD provides critical information about physical state of solutes during freezing, annealing and in the final lyophile.

Professor Raj Suryanarayanan: Scientist, Educator, Mentor, Family Man and Giant in Pharmaceutical Research.

This special edition of the Journal of Pharmaceutical Sciences is dedicated to Professor Raj Suryanarayanan (Professor and William & Mildred Peters Endowed Chair, University of Minnesota, School of Pharmacy) and honors his extensive and distinguished career as a scientist, educator and mentor. The goal of this commentary is to provide an overview of Professor Suryanarayanan's noteworthy career path and summarize his key research contributions. The commentary concludes with the personal summaries by guest editors.

Mannitol as an Excipient for Lyophilized Injectable Formulations.

The review summarizes the current state of knowledge of mannitol as an excipient in lyophilized injectable small and large molecule formulations. When compared with glycine, the physicochemical properties of mannitol make it a desirable and preferred bulking agent. Though mannitol is a popular bulking agent in freeze-dried formulations, its use may pose certain challenges such as vial breakage or its existence as a metastable crystalline hemihydrate in the final cake, necessitating appropriate mitigation strategies.

Mannitol hemihydrate in lyophilized protein formulations:Impact of its dehydration during storage on sucrose crystallinity and protein stability.

The high propensity of mannitol to crystallize in frozen solutions along with its high eutectic temperature enabling higher primary drying temperatures makes it a good bulking agent. In protein formulations, addition of a sugar (sucrose) that has the ability to remain amorphous throughout processing as well as storage is imperative to retain the protein in its native state. It is well known that in the presence of amorphous excipients and protein, mannitol can crystallize as a mixture of anhydrous polymorphs - α-, β- and δ-forms and a hemihydrate form [mannitol hemihydrate (MHH); CHO·0.

Reversible Self-Association in Lactate Dehydrogenase during Freeze-Thaw in Buffered Solutions Using Neutron Scattering.

The aims of this work were to evaluate the effect of freezing and thawing stresses on lactate dehydrogenase (LDH) stability under three conditions. (i) In a solution buffered with sodium phosphate (NaP; 10 and 100 mM). The selective crystallization of disodium hydrogen phosphate during freezing caused a pronounced pH shift.

Stabilizers and their interaction with formulation components in frozen and freeze-dried protein formulations.

This review aims to provide an overview of the current knowledge on protein stabilization during freezing and freeze-drying in relation to stress conditions commonly encountered during these processes. The traditional as well as refined mechanisms by which excipients may stabilize proteins are presented. These stabilizers encompass a wide variety of compounds including sugars, sugar alcohols, amino acids, surfactants, buffers and polymers.

Anomalous behavior of mannitol hemihydrate: Implications on sucrose crystallization in colyophilized systems.

When solutions containing mannitol and sucrose are freeze-dried, depending on the processing conditions and the formulation composition, mannitol can crystallize in the anhydrous form, as mannitol hemihydrate (MHH; CHO·0.5HO) or as a mixture of the two. The retention of MHH in the final lyophile, and its dehydration during product storage could lead to instability of the final drug product.

-Butanol Enables Dual Functionality of Mannitol: A Cryoprotectant in Frozen Systems and Bulking Agent in Freeze-Dried Formulations.

The effect of tertiary butyl alcohol (TBA) as a cosolvent on the phase behavior of mannitol in frozen and freeze-dried systems was characterized using differential scanning calorimetry (DSC) and X-ray diffractometry (XRD; laboratory and synchrotron sources). Solutions of mannitol (2 and 5% w/w) in TBA-water systems of different compositions (5 to 30% w/w TBA) were characterized, both during cooling and warming using DSC and XRD. At and below the TBA-water eutectic composition (22.

Asymmetric in-plane shear behavior of isolated cadaveric lumbar facet capsular ligaments: Implications for subject specific biomechanical models.

The facet capsular ligaments (FCLs) flank the spinous process on the posterior aspect of the spine. The lumbar FCL is collagenous, with collagen fibers aligned primarily bone-to-bone (medial-lateral) and experiences significant shear, especially during spinal flexion and extension. We characterized the mechanical response of the lumbar FCL to in-plane shear, and we evaluated that response in the context of the fiber architecture.

Role of Lattice Disorder in Water-Mediated Dissociation of Pharmaceutical Cocrystal Systems.

Our objective is to mechanistically understand the implications of processing-induced lattice disorder on  the stability of pharmaceutical cocrystals. Caffeine-oxalic acid (CAFOXA) and dicalcium phosphate anhydrate (DCPA) were the model cocrystal (drug) and excipient, respectively. Cocrystal-excipient mixtures were milled for short times (≤2 min) and stored at room temperature (RT)/75% RH.

Compression-Induced Polymorphic Transformation in Tablets: Role of Shear Stress and Development of Mitigation Strategies.

Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets.

Applications of Powder X-Ray Diffraction in Small Molecule Pharmaceuticals: Achievements and Aspirations.

Since the discovery of X-ray diffraction and its potential to elucidate crystal symmetry, powder X-ray diffraction has found diverse applications in the field of pharmaceutical sciences. This review summarizes significant achievements of the technique during various stages of dosage form development. Improved understanding of the principle involved and development of automated hardware and reliable software have led to increased instrumental sensitivity and improved data analysis.

Evaluation of novel formulations of d-β-hydroxybutyrate and melatonin in a rat model of hemorrhagic shock.

d-β-hydroxybutyrate and melatonin (BHB/MLT) infusion improves survival in hemorrhagic shock models. The original BHB/MLT formulation contains dimethyl sulfoxide (DMSO) to increase melatonin solubility. We formulated BHB/MLT solutions wherein DMSO was replaced either with 10% polyvinylpyrrolidone (BHB/MLT/PVP) or with 5% hydroxypropyl-β-cyclodextrin/2.

Effect of Formulation and Process Parameters on the Disproportionation of Indomethacin Sodium in Buffered Lyophilized Formulations.

Purpose: (i) To investigate buffer salt crystallization and the consequent pH shifts during the freezing stage of the lyophilization of indomethacin sodium (IMCNa) in aqueous sodium phosphate buffer. (ii) To determine the effect of pH shift on the disproportionation of IMCNa in lyophilized formulations.

Methods: Prelyophilization solutions containing IMCNa in sodium phosphate buffer, at initial buffer concentrations ranging from 10 to 100 mM (pH 7.

Development and in vivo evaluation of a novel lyophilized formulation for the treatment of hemorrhagic shock.

Hemorrhagic shock, caused by trauma, is a leading cause of preventable death. A combination treatment of d-β-hydroxybutyrate (BHB) and melatonin (MLT), in dimethyl sulfoxide - water, increased survival. A freeze-dried BHB-MLT formulation, with a short reconstitution time, has been developed.

Estimation of Drug Particle Size in Intact Tablets by 2-Dimensional X-Ray Diffractometry.

The average grain size of a crystalline material can be determined from the γ-profile of Debye rings in 2-dimensional X-ray diffraction frames. Our objectives were to: (1) validate the method for organic powders and use it to determine the grain size in intact tablets, and (2) demonstrate the pharmaceutical application of this technique by determining the grain size of the active pharmaceutical ingredient in marketed formulations. Six sieve fractions of sucrose were prepared and the particle size distribution was confirmed by laser diffraction.

Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory-Huggins Theory.

Drug-polymer miscibility is one of the fundamental prerequisite for the successful design and development of amorphous solid dispersion formulation. The purpose of the present work is to provide an example of the theoretical estimation of drug-polymer miscibility and solubility on the basis of Flory-Huggins (F-H) theory and experimental validation of the phase diagram. The F-H interaction parameter, χ d-p, of model system, aceclofenac and Soluplus, was estimated by two methods: by melting point depression of drug in presence of different polymer fractions and by Hildebrand and Scott solubility parameter calculations.

Salt formation during freeze-drying--an approach to enhance indomethacin dissolution.

Purpose: (i) Prepare a freeze-dried injectable indomethacin (IMC) dosage form. (ii) Convert IMC to its tris salt during freeze-drying so as to facilitate rapid dissolution (reconstitution). (iii) Modulate salt crystallinity by annealing the frozen solution.

Instability in theophylline and carbamazepine hydrate tablets: cocrystal formation due to release of lattice water.

Purpose: To demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior.

Methods: Tablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40°C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured.

Eudragit: a technology evaluation.

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

Areas Covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed.

Urea co-inclusion compounds of 13 cis-retinoic acid for simultaneous improvement of dissolution profile, photostability and safe handling characteristics.

13-cis Retinoic acid (cis-RA), a synthetic retinoid used in the treatment of severe acne, is known to exhibit extremely low aqueous solubility and high photosensitivity. In this study, urea, a well-known adductor for linear compounds, was successfully employed for the adduction of cis-RA - a substituted cyclic organic compound. Formation of urea inclusion compounds was confirmed by FTIR, DSC and XRD.

Urea inclusion compounds of enalapril maleate for the improvement of pharmaceutical characteristics.

Urea is a well known adductor for linear organic compounds. In the present study, enalapril maleate, a substituted cyclic organic compound, was successfully included in urea together with a suitable rapidly adductible endocyte (RAE). Formation of the urea inclusion compound was confirmed by Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction.