Role of Heteronucleants in Melt Crystallization of Crystalline Solid Dispersions.

Few publications exist concerning polymorphic control during melt crystallization, particularly when employing heteronucleants. Here, the influence of a polymeric thin film (polyethylene terephthalate, PET) on the crystallization from melt of the polymorphic compound acetaminophen (ACM) in polyethylene glycol (PEG) was investigated. Molten ACM-PEG at different compositions was monitored using in situ Raman spectroscopy for nucleation induction time measurements and phase identification.

High-Affinity Extended Bisphosphonate-Based Coordination Polymers as Promising Candidates for Bone-Targeted Drug Delivery.

Extended bisphosphonate-based coordination polymers (BPCPs) were produced when 1,1'-biphenyl-4,4'-bisphosphonic acid (BPBPA), the analogue of 1,1'-biphenyl-4,4'-dicarboxylic acid (BPDC), reacted with bioactive metals (Ca, Zn, and Mg). BPBPA-Ca (11 Å × 12 Å), BPBPA-Zn (10 Å × 13 Å), and BPBPA-Mg (8 Å × 11 Å) possess channels that allow the encapsulation of letrozole (LET), an antineoplastic drug that combined with BPs treats breast-cancer-induced osteolytic metastases (OM). Dissolution curves obtained in phosphate-buffered saline (PBS) and fasted-state simulated gastric fluid (FaSSGF) demonstrate the pH-dependent degradation of BPCPs.

Design of Extended Bisphosphonate-Based Coordination Polymers as Bone-Targeted Drug Delivery Systems for Breast Cancer-Induced Osteolytic Metastasis and Other Bone Therapies.

The coordination between benzene 1,4-bis(bisphosphonic acid) (BBPA), the bisphosphonate (BP) analogue of benzene 1,4-dicarboxylic acid (BDC), and bioactive metals led to the formation of extended bisphosphonate-based coordination polymers (BPCPs). Four distinct crystalline phases were obtained, namely, BBPA-Ca forms I and II, BBPA-Zn, and BBPA-Mg. Among these, BBPA-Ca forms I (7 × 9 Å) and II (8 × 12 Å) possess channels large enough to encapsulate 5-fluorouracil (5-FU), a drug prescribed in combination with BPs to treat breast cancer-induced osteolytic metastases (OM).

Beyond Antiresorptive Activity: Risedronate-Based Coordination Complexes To Potentially Treat Osteolytic Metastases.

Coordination of clinically employed bisphosphonate, risedronate (RISE), to bioactive metals, Ca, Mg, and Zn, allowed the formation of bisphosphonate-based coordination complexes (BPCCs). Three RISE-based BPCCs, RISE-Ca, RISE-Mg, and RISE-Zn, were produced, and their structures were elucidated by single crystal X-ray diffraction. Interestingly, the addition of an auxiliary ligand, etidronic acid (HEDP), resulted in the recrystallized protonated form of the ligand, H-RISE.

Polymorphic control in titanium dioxide particles.

The hydrolysis-condensation reaction of TiO was adapted to the phase inversion temperature (PIT)-nano-emulsion method as a low energy approach to gain control over the size and phase purity of the resulting metal oxide particles. Three different PIT-nano-emulsion syntheses were designed, each one intended to isolate high purity rutile, anatase, and brookite phase particles. Three different emulsion systems were prepared, with a pH of either strongly acidic (HO : HNO, pH ∼0.

Functionalization of Titanium Dioxide by Surface Crystallization of Bisphosphonate-Based Coordination Complexes.

Functionalization of highly pure rutile phase titanium dioxide (TiO) particles with a selected bisphosphonate-based coordination complex (BPCC), ZOLE-Ca form II, was achieved through in situ surface crystallization. The hydrothermal reaction of the selected BPCC was carried out in the presence of photoactivated rutile phase TiO by ultraviolet irradiation. The reaction time was varied to control the crystal growth of the BPCC around the TiO core, resulting in a functionalized material with different shell thicknesses: TiO-core:ZOLE-shell-† (5 min) and TiO-core:Ca@ZOLE-shell-‡ (10 min).

Solvent-Mediated Polymorphic Transformations in Molten Polymers: The Account of Acetaminophen.

Solvent-mediated polymorphic transformations (SMPTs) employing nonconventional solvents (polymer melts) is an underexplored research topic that limits the application of polymer-based formulation processes. Acetaminophen (ACM), a widely studied active pharmaceutical ingredient (API), is known to present SMPTs spontaneously (<30 s) in conventional solvents such as ethanol. Raman spectroscopy was employed to monitor the induction time for the SMPT of ACM II to I in polyethylene glycol (PEG) melts of different molecular weights (, 4000, 10 000, 20 000, 35 000 g/mol).

High affinity zoledronate-based metal complex nanocrystals to potentially treat osteolytic metastases.

Formation of several materials, denoted as bisphosphonate-based coordination complexes (BPCCs), resulted from the reaction between clinically employed bisphosphonate, zoledronate (ZOLE) and bioactive metals (M = Ca, Mg and Zn). Six ZOLE-based BPCCs were synthesized using different variables (M : ZOLE molar ratio, temperature, pH, and anion) and their structures were elucidated by single crystal X-ray diffraction (ZOLE-Ca forms I and II, ZOLE-Mg forms I and II, and ZOLE-Zn forms I and II). The dissolution of the ZOLE-based BPCCs was compared to that of ZOLE (Reclast®).

Real-time concentration monitoring using a compact composite sensor array for in situ quality control of aqueous formulations.

Recent advancements have demonstrated the feasibility of refrigerator-sized pharmaceutical manufacturing platforms (PMPs) for integrated end-to-end manufacturing of active pharmaceutical ingredients (APIs) into formulated drug products. Unlike typical laboratory- or industrial-scale setups, PMPs present unique requirements for process analytical technology (PAT) with respect to versatility, flexibility, and physical size to fit into the PMP space constraints. In this proof of principle study, a novel compact composite sensor array (CCSA) combining ultraviolet (UV) and near infrared (NIR) features at four different wavelengths (280, 340, 600, 860 nm) with temperature measuring capability in a 380 × 30 mm housing (length x diameter, 7 mm diameter at the probe head), were evaluated.

Polymorphism in early development: The account of MBQ-167.

With McCrone's famous statement in mind, we set out to investigate the polymorphic behavior of a small-molecule dual inhibitor of Rac and Cdc42, currently undergoing preclinical trials. Herein, we report the existence of two polymorphs for 9-ethyl-3-(5-phenyl-1H-1,2,3-triazol-3-yl)-9H-carbazole (MBQ-167). These were characterized by differential scanning calorimetry, thermogravimetric analysis, Raman and Infrared spectroscopy, as well as powder and single crystal X-ray diffraction.

Solubility Measurements and Correlation of MBQ-167 in Neat and Binary Solvent Mixtures.

MBQ-167 is a novel, small-molecule dual inhibitor of Rac and Cdc42, small GTPases that are involved in cytoskeletal organization, cell cycle progression, and cell migration. In an mouse model, MBQ-167 has been shown to significantly reduce mammary tumor growth and metastasis and is currently undergoing preclinical studies for the treatment of metastatic cancer. To date, no solubility data have been reported for this compound.

Design of Potential Pharmaceutical-Based Metal Complexes Derived from Cromolyn a Mast Cell Stabilizer.

A series of pharmaceutical metal complexes (pMCs) were produced and characterized using the mast cell stabilizer, cromolyn, and bioactive metal ions (Zn, Mg, and Ca). Three novel pMCs, Cromolyn-Zn, Cromolyn-Mg, and Cromolyn-Ca, were formed through reactions under controlled temperature and pH conditions. Additional characterization for these materials was performed employing a number of solid-state characterization techniques, such as thermogravimetric analysis (TGA), powder and single-crystal X-ray diffraction (PXRD and SCXRD), and scanning electron microscopy coupled with energy-dispersive spectroscopy (SEM-EDS).

A deltamethrin crystal polymorph for more effective malaria control.

Pyrethroid contact insecticides are mainstays of malaria control, but their efficacies are declining due to widespread insecticide resistance in mosquito populations, a major public health challenge. Several strategies have been proposed to overcome this challenge, including insecticides with new modes of action. New insecticides, however, can be expensive to implement in low-income countries.

Genotype-driven pharmacokinetic simulations of warfarin levels in Puerto Ricans.

Objectives The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans. Methods Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.

Genotype-driven pharmacokinetic simulations of warfarin levels in Puerto Ricans.

Objectives: The inter-individual variability of warfarin dosing has been linked to genetic polymorphisms. This study was aimed at performing genotype-driven pharmacokinetic (PK) simulations to predict warfarin levels in Puerto Ricans.

Methods: Analysis of each individual dataset was performed by one-compartmental modeling using WinNonlin®v6.

Potentiating bisphosphonate-based coordination complexes to treat osteolytic metastases.

The hydrothermal reaction between bioactive metal (Ca2+, Zn2+, and Mg2+) salts and a clinically utilized bisphosphonate, alendronate (ALEN), promotes the formation of several materials denominated as bisphosphonate-based coordination complexes (BPCCs). The systematic exploration of the effect of three variables, M2+/ALEN molar ratio, temperature, and pH, on the reaction yielded an unprecedented number of materials of enough crystal quality for structural elucidation. Five crystal structures were unveiled by single crystal X-ray diffraction (ALEN-Ca forms I and II, ALEN-Zn forms I and II, and ALEN-Mg) and their solid-state properties revealed in tandem with other techniques.

Polymorphism in Solid Dispersions.

Solid dispersions embed active pharmaceutical ingredients in polymeric carriers to improve their solubility. Three solid dispersion preparation techniques are typically employed: solvent evaporation, solvent-fusion, and fusion methods. Although these are also widely recommended as preparative methods for phase diagram determination, few examples exist concerning their effect on the resulting polymorph, once the solid dispersion is produced.

Solubility Determination and Correlation of Warfarin Sodium 2‑Propanol Solvate in Pure, Binary, and Ternary Solvent Mixtures.

The solubility of warfarin sodium isopropanol solvate (WS·IPA), a widely used anticoagulant, was determined at temperatures ranging from 278.15 to 333.15 K in four pure solvents (acetone, ethanol, IPA, and water), five binary solvent mixtures (IPA + acetone, IPA + ethanol, IPA + water, IPA + heptane, and IPA + hexane), and five ternary solvent mixtures (IPA + acetone + heptane, IPA + acetone + hexane, IPA + ethanol + heptane, IPA + ethanol + hexane, and IPA + water + heptane) using the polythermal method.

In the Context of Polymorphism: Accurate Measurement, and Validation of Solubility Data.

Solubility measurements for polymorphic compounds are often accompanied by solvent-mediated phase transformations. In this study, solubility measurements from undersaturated solutions are employed to investigate the solubility of the two most stable polymorphs of flufenamic acid (FFA forms I and III), tolfenamic acid (TA forms I and II), and the only known form of niflumic acid (NA). The solubility was measured from 278.

Measurement and Correlation of the Solubility of 5-Fluorouracil in Pure and Binary Solvents.

The solubility of 5-ffuorouracil (5-FU), a widely used chemotherapeutic agent to treat solid tumors, which include colorectal, head and neck, breast, and lung cancer, was determined at temperatures ranging from 278.15 to 333.15 K in 11 pure solvents and binary water + ethanol solvent mixtures using the polythermal method.

Revealing Polymorphic Phase Transformations in Polymer-Based Hot Melt Extrusion Processes.

The inadvertent occurrence of polymorphic phase transformations in active pharmaceutical ingredients (APIs) during hot melt extrusion (HME) processes has been claimed to limit the application of this technique. Hence, the control of polymorphism would need to be addressed if there is any prospect of HME to be successfully implemented as an alternative solid dosage formulation strategy in integrated, continuous end-to-end pharmaceutical manufacturing settings. This work demonstrates that flufenamic acid (FFA), one of the most polymorphic APIs known, thus far, can be processed using temperature-simulated HME with polyethylene glycol (PEG) as polymeric carrier.

Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures.

The unprecedented polymorphism of the non-steroidal anti-inflammatory drug (NSAID) flufenamic acid (FFA) is described here. Nine polymorphs were accessed through the use of polymer-induced heteronucleation (PIHn) and solid-solid transformation at low temperature. Structural elucidation of six of these forms, in addition to the two previously known forms, makes FFA indisputably octamorphic.

On the mechanism of crystalline polymorph selection by polymer heteronuclei.

The phase-selective crystallization of acetaminophen (ACM) using insoluble polymers as heteronuclei was investigated in a combined experimental and computational effort to elucidate the mechanism of polymer-induced heteronucleation (PIHn). ACM heteronucleates from supersaturated aqueous solution in its most thermodynamically stable monoclinic form on poly(n-butyl methacrylate), whereas the metastable orthorhombic form is observed on poly(methyl methacrylate). When ACM crystals were grown through vapor deposition, only the monoclinic polymorph was observed on each polymer.