Phase Transitions Involving Channel Hydrates of a New Pharmaceutical Compound.

INTRODUCTION: Hydrates are often used as pharmaceutical active pharmaceutical ingredients (API), especially when anhydrates may not be feasible likely due to physicochemical properties concerns. Pharmaceutical hydrates, whereas water is present as crystal adduct, are feasible for drug products as they do not pose any safety concern. Hydrates can impart many different advantages; therefore, they are quite common and preferred solid forms for numerous pharmaceutical materials on market. However, hydrates may involve various phase transitions, which may impact the stability and processability of drug substance. METHODS: Phase transitions, which include temperature-induced dehydration and moisture-facilitated rehydration are investigated by different solid-state analytical techniques such as powder x-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, polarized light microscopy, and single-crystal x-ray diffraction. RESULTS: This research investigation focuses on the different phase transition behaviors of a newly discovered pharmaceutical compound with three channel hydrates, two of which confirmed by single-crystal analysis. The retention or rearrangement of crystal structures over the transitions are studied. Hydrate 3 exhibits a characteristic feature of channel hydrate that involves symmetric lattice relaxation. Unlike hydrate 3, hydrate 2 results in a potentially new unit cell upon dehydration due to asymmetric lattice relaxation, which converted back to Hydrate 2 in presence of water, a very unique behavior for a channel hydrate, rarely observed, which entails novelty of this research work. CONCLUSION: The relationship among crystal forms of different hydrates of this new compound is thus established. The current investigation is a vital part of drug product risk assessment for hydrates to avoid any challenges during manufacturing operations and/or stability studies. This investigation was successfully applied in the present study and can be expanded to other newly discovered APIs in future.

Computational and Experimental Screening Approaches to Aripiprazole Salt Crystallization.

INTRODUCTION: The screening of multicomponent crystal system (MCC) is a key method for improving physicochemical properties of active pharmaceutical ingredients (APIs). The challenges associated with experimental salt screening include a large number of potential counterions and solvent systems and tendency to undergo disproportionation to produce free form during crystallization. These challenges may be mitigated by a combination of experimental and computational approaches to salt screening. The goal of this study is to evaluate performance of the counterion screening methods and propose and validate novel approaches to virtual solvent screening for MCC crystallization. METHODS: The actual performance of the ΔpKa > 3 rule for counterion selection was validated using multiple screenings reports. Novel computational models for virtual solvent screening to avoid MCC incongruent crystallization were proposed. Using the ΔpKa rule, 10 acid counterions were selected for experimental aripiprazole (APZ) salt screening using 10 organic solvents. The experimental results were used to validate the proposed novel virtual solvent screen models. RESULTS: Experimental APZ salt screening resulted in a total of eight MCCs which included glucuronate, mesylate, oxalate, tartrate, salicylate and mandelate. The new model to virtually screen solvents provided a general agreement with APZ experimental findings in terms of selecting the optimal solvent for MCC crystallization. CONCLUSION: The rational selection of counterions and organic solvents for MCC crystallization was presented using combined novel computational model as well as experimental studies. The current virtual solvent screen model was successfully implemented and validated which can be easily applied to newly discovered APIs.

Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations.

Establishing the absolute configuration of chiral active pharmaceutical ingredients (APIs) is of great importance. Single crystal X-ray diffraction (scXRD) has traditionally been the method of choice for such analysis, but scXRD requires the growth of large crystals, which can be challenging. Here, we present a method for determining absolute configuration that does not rely on the growth of large crystals. By examining microcrystals formed with chiral probes (small chiral compounds such as amino acids), absolute configuration can be unambiguously determined by microcrystal electron diffraction (MicroED). Our streamlined method employs three steps: (1) virtual screening to identify promising chiral probes, (2) experimental cocrystal screening and (3) structure determination by MicroED and absolute configuration assignment. We successfully applied this method to analyze two chiral API molecules currently on the market for which scXRD was not used to determine absolute configuration.

pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs.

PURPOSE: In amorphous solid dispersions (ASDs), the chemical potential of a drug can be reduced due to mixing with the polymer in the solid matrix, and this can lead to reduced drug release when the polymer is insoluble in the dissolution media. If both the drug and the polymer composing an ASD are ionizable, drug release from the ASD becomes pH-dependent. The goal of this study was to gain insights into the pH-dependent solubility suppression from ASD formulations. METHODS: The maximum release of clotrimazole, a weakly basic drug, from ASDs formulated with insoluble and pH-responsive polymers, was determined as a function of solution pH. Drug-polymer interactions in ASDs were probed using melting point depression, moisture sorption, and solid-state Nuclear Magnetic Resonance spectroscopy (SSNMR) measurements. RESULTS: The extent of solubility suppression was dependent on polymer type and drug loading. The strength of drug-polymer interactions was found to correlate well with the degree of solubility suppression. For the same ASD, the degree of solubility suppression was nearly constant across the solution pH range studied, suggesting that polymer-drug interactions in residual ASD solids was independent of solution pH. The total drug release agrees with the Henderson-Hasselbalch relationship if the suppressed amorphous solubility of the free drug is independent of solution pH. CONCLUSIONS: The mechanism of solubility suppression at different solution pHs appeared to be drug-polymer interactions in the solid-state, where the concentration of the free drug remains the same at variable pHs and the total drug concentration follows the Henderson-Hasselbalch relationship.

Accelerating pre-formulation investigations in early drug product life cycles using predictive methodologies and computational algorithms.

Precisely developed computational methodologies can allow the drug product lifecycle process to be time-efficient, cost-effective and reliable through a thorough fundamental understanding at the molecular level. Computational methodologies include computational simulations, virtual screening, mathematical modeling and predictive tools. In light of current trends and increased expectations of product discovery in early pharmaceutical development, we have discussed different case studies. These case studies clearly demonstrate the successful application of predictive tools alone or in combination with analytical techniques to predict the physicochemical properties of drug substances and drug products, thereby shortening research and development timelines. The overall goal of this report is to summarize unique predictive methodologies, which can assist pharmaceutical scientists in achieving time-sensitive research goals and avoiding associated risks that can potentially affect the drug product quality.

Crystal form control and particle size control of RG3487, a nicotinic α7 receptor partial agonist.

This paper describes solid form control and particle size control of RG3487, a nicotinic receptor partial agonist. Four crystal forms were identified by polymorph screen under ∼100 varying conditions. Form A and Form B are anhydrates, while Forms C and D are solvates. Forms A, which is enantiotropically related to Form B, is the more thermodynamically stable form under ambient conditions and the desired form selected for clinical development. The crystal form control of Form A was achieved by crystallization solvent selection which consistently produced the desired form. Several process parameters impacting particle size of Form A in the final crystallization step were identified and investigated through both online and offline particle size measurement. The investigation results were utilized to control crystallization processes which successfully produced Form A with different particle size in 500g scale.

Synthesis and structural characterization of Cu(I) and Ni(II) complexes that contain the bis[2-(diphenylphosphino)phenyl]ether ligand. Novel emission properties for the Cu(I) species.

The pseudotetrahedral complexes [Cu(NN)(DPEphos)]BF(4), where DPEphos = bis[2-(diphenylphosphino)phenyl]ether and NN = 1,10-phenanthroline (1), 2,9-dimethyl-1,10-phenanthroline (2), 2,9-di-n-butylphenanthroline (3), or two dimethylcyanamides (4), and NiCl(2)(DPEphos) (5) have been synthesized and structurally characterized by X-ray crystallography and their solution properties examined by use of a combination of cyclic voltammetry, NMR spectroscopy, and electronic absorption spectroscopy. Complexes 1-4 possess a reversible Cu(II)/Cu(I) couple at potentials upward of +1.2 V versus Ag/AgCl. Compounds 1-3 exhibit extraordinary photophysical properties. In room-temperature dichloromethane solution, the charge-transfer excited state of the dmp (dbp) derivative exhibits an emission quantum yield of 0.15 (0.16) and an excited-state lifetime of 14.3 mus (16.1 mus). Coordinating solvents quench the charge-transfer emission to a degree, but the photoexcited dmp complex 2 retains a lifetime of over a microsecond in acetone, methanol, and acetonitrile.

A new type of tweezer complex involving a rhenium-rhenium multiple bond that enforces an unusual structure in a dipalladium(II) unit.

The substitution of the mu-acetato ligands in cis-Re(2)(mu-O(2)CCH(3))(2)Cl(2)(mu-dppm)(2) (1, dppm = Ph(2)PCH(2)PPh(2)) and trans-Re(2)(mu-O(2)CCH(3))(2)Cl(2)(mu-dppE)(2) (2, dppE = Ph(2)PC(=CH(2))PPh(2)) by [4-Ph(2)PC(6)H(4)CO(2)](-) occurs with retention of stereochemistry to give cis-Re(2)(mu-O(2)CC(6)H(4)-4-PPh(2))(2)Cl(2)(mu-dppm)(2) (3) and trans-Re(2)(mu-O(2)CC(6)H(4)-4-PPh(2))(2)Cl(2)(mu-dppE)(2) (6), respectively. The uncoordinated phosphine groups in complexes 3 and 6 have been used to form mixed-metal assemblies with Au(I) and Pd(II), including the Re(2)Pd(2) complex cis-Re(2)(mu-O(2)CC(6)H(4)-4-PPh(2))(2)Cl(2)(mu-dppm)(2)(Pd(2)Cl(4)) (5), in which the planar [(P)ClPd(mu-Cl)(2)PdCl(P)] unit has the unusual cis structure. The crystal structures of 3 and 5 have been determined.

Simple Cu(I) complexes with unprecedented excited-state lifetimes.

This report describes new, readily accessible copper(I) complexes that can exhibit unusually long-lived, high quantum yield emissions in fluid solution. The complexes are of the form [Cu(NN)(POP)]+ where NN denotes 1,10-phenanthroline (phen), 2,9-dimethyl-1,10-phenanthroline (dmp) or 2,9-di-n-butyl-1,10-phenanthroline (dbp) and POP denotes bis[2-(diphenylphosphino)phenyl] ether. Modes of characterization include X-ray crystallography and cyclic voltammetry. The complexes each have a pseudotetrahedral coordination geometry and a Cu(II)/Cu(I) potential upward of +1.2 V vs Ag/AgCl. In room-temperature dichloromethane solution, charge-transfer excited states of the dmp and dbp derivatives exhibit respective emission quantum yields of 0.15 and 0.16 and corresponding excited-state lifetimes of 14.3 and 16.1 mus, respectively. Despite the fact that coordinating solvents usually quench charge-transfer emission from copper systems, the photoexcited dmp (dbp) complex retains a lifetime of 2.4 mus (5.4 mus) in methanol.

Unsymmetrical dirhenium complexes that contain [Re(2)](6+) and [Re(2)](5+) cores complexed by tridentate ligands with P(2)O and P(2)N donor sets.

The quadruply bonded dirhenium(III) complex (n-Bu(4)N)(2)Re(2)Cl(8) reacts with tridentate ligands that contain essentially planar P,O,P donor sets to afford the complexes Re(2)Cl(6)(eta(3)-L(1)) (3) (L(1) = bis[2-(diphenylphosphino)phenyl]ether) and (n-Bu(4)N)[Re(2)Cl(7)(eta(1)-L(2))] (4) (L(2) = 4,6-bis(diphenylphosphino)dibenzofuran). Spectroscopic and electrochemical data support the unsymmetrical structure Cl(4)ReReCl(2)(eta(3)-L(1)) in the case of 3, while 4 contains monodentate P-bound L(2) both complexes contain Re---Re bonds. The synthon cis-Re(2)(mu-O(2)CCH(3))(2)Cl(4)(H(2)O)(2) reacts with ligands L(1), L(2), 2,6-bis(diphenylphosphinomethyl)pyridine (L(3)), bis[2-(diphenylphosphino)ethyl]amine (L(4)), and N,N-bis[2-(diphenylphosphino)ethyl]trimethylacetamide (L(5)) to give the paramagnetic complexes Re(2)(mu-O(2)CCH(3))Cl(4)(eta(3)-L(n)) (5-9) with Re bonds. The lability of the mu-acetato ligands in 5-9 has been demonstrated by the reactions of compounds 5 (n = 1) and 7 (n = 3) with 4-Ph(2)PC(6)H(4)CO(2)H, 2-Ph(2)PC(6)H(4)CO(2)H, and quinoline-4-carboxylic acid to give complexes 10-12 (from 5) and 13-15 (from 7), respectively. These products contain uncoordinated donor atoms that can be used to produce mixed-metal assemblies. Compounds 5 and 7 also react with terephthalic acid (1,4-C(6)H(4)(CO(2)H) to give [Re(2)Cl(4)(eta(3)-L(1))](2)(mu-O(2)CC(6)H(4)CO(2)) (16) and [Re(2)Cl(4)(eta(3)-L(3))](2)(mu-O(2)CC(6)H(4)CO(2)) (17) in which electronic coupling between the paramagnetic sets of dirhenium units is very weak. Single-crystal X-ray structure determinations have been carried out on complexes 5-8, 11, 12, and 14-16.