Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the Antipsychotic Drug Aripiprazole (Abilify)

Crystal form exploration of dehydro-aripiprazole (dAPZ), the active metabolite of the antipsychotic drug aripiprazole (APZ), elucidated five polymorphs (I, II, III, IV, and V), two methanol solvates, and a monohydrate. The forms were characterized by thermal microscopy, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), single and powder X-ray diffraction (SCXRD and PXRD), and infrared spectroscopy. DSC analysis showed monotropic relationships among polymorphs I, II, III, and IV and enantiotropic relationships for the two form pairs I ↔ V and II ↔ V. Solvent-mediated conversion experiments indicated that Form V is the thermodynamically stable form in the temperature range 5–60 °C and Form I is the stable form at ≥70 °C, where a transition temperature lies between 60 and 70 °C. Two polymorphs of the methanol solvate (S_MeOH1 and S_MeOH2) were crystallized from methanol solutions in 1:1 dAPZ/methanol molar ratio. S_MeOH2 is the thermodynamically stable form of the two methanol solvates at ambient temperature. The monohydrate (S_H₂O) was obtained by solvent-mediated conversion experiments of any of the methanol solvates in water. Single-crystal structure analysis of polymorphs I, II, V and the two methanol solvates showed the formation of dimeric structures with N–H···OC (amide–amide) hydrogen-bonded homodimer synthons. In the case of S_H₂O, two water molecules are present between the units of the dimer, and each water molecule exhibits hydrogen-bonding with one of the piperazine nitrogen atoms of a third dAPZ molecule. Analysis of the crystal structures and PXRD patterns for both the APZ and dAPZ nonsolvated polymorphs reveals that all the forms are distinct from one another. When solvates and hydrates were added to the comparison (a total of 18 crystalline forms of APZ and dAPZ), only S_MeOH2 of dAPZ was found to have an identical packing arrangement to the APZ methanol solvate. This study illustrates that despite the chemical structure similarity between dAPZ and APZthe differences being one CC double-bond vs a C–C single-bond and a molecular weight change of 2 Da out of 448the observed crystal packing arrangement in the polymorphs of the active metabolite differs significantly from those observed for the parent drug

Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the Antipsychotic Drug Aripiprazole (Abilify)

Crystal form exploration of dehydro-aripiprazole (dAPZ), the active metabolite of the antipsychotic drug aripiprazole (APZ), elucidated five polymorphs (I, II, III, IV, and V), two methanol solvates, and a monohydrate. The forms were characterized by thermal microscopy, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), single and powder X-ray diffraction (SCXRD and PXRD), and infrared spectroscopy. DSC analysis showed monotropic relationships among polymorphs I, II, III, and IV and enantiotropic relationships for the two form pairs I ↔ V and II ↔ V. Solvent-mediated conversion experiments indicated that Form V is the thermodynamically stable form in the temperature range 5–60 °C and Form I is the stable form at ≥70 °C, where a transition temperature lies between 60 and 70 °C. Two polymorphs of the methanol solvate (S_MeOH1 and S_MeOH2) were crystallized from methanol solutions in 1:1 dAPZ/methanol molar ratio. S_MeOH2 is the thermodynamically stable form of the two methanol solvates at ambient temperature. The monohydrate (S_H₂O) was obtained by solvent-mediated conversion experiments of any of the methanol solvates in water. Single-crystal structure analysis of polymorphs I, II, V and the two methanol solvates showed the formation of dimeric structures with N–H···OC (amide–amide) hydrogen-bonded homodimer synthons. In the case of S_H₂O, two water molecules are present between the units of the dimer, and each water molecule exhibits hydrogen-bonding with one of the piperazine nitrogen atoms of a third dAPZ molecule. Analysis of the crystal structures and PXRD patterns for both the APZ and dAPZ nonsolvated polymorphs reveals that all the forms are distinct from one another. When solvates and hydrates were added to the comparison (a total of 18 crystalline forms of APZ and dAPZ), only S_MeOH2 of dAPZ was found to have an identical packing arrangement to the APZ methanol solvate. This study illustrates that despite the chemical structure similarity between dAPZ and APZthe differences being one CC double-bond vs a C–C single-bond and a molecular weight change of 2 Da out of 448the observed crystal packing arrangement in the polymorphs of the active metabolite differs significantly from those observed for the parent drug

Crystal Engineering of Isostructural Quaternary Multicomponent Crystal Forms of Olanzapine

Pharmaceutical cocrystals have gained increased attention at least in part because of their potential for enhancing physicochemical and biopharmaceutical properties of existing drugs. As a result, design, screening, and large-scale preparation of pharmaceutical cocrystals have been emphasized in recent research. The design of pharmaceutical cocrystals has focused primarily on determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach is typically less predictive when considering drugs that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. In this manuscript, we report a crystal engineering design strategy to facilitate the synthesis of multicomponent crystal forms of the atypical antipsychotic drug olanzapine, marketed as a drug product under the trade name Zyprexa. Comprehensive analysis and data mining of existing crystal structures of olanzapine were followed by grouping into categories according to the crystal packing exhibited and systematically using this information to crystal engineer new compositions. This approach afforded isostructural, quaternary multicomponent crystal forms of olanzapine composed of a stoichiometric ratio of four molecular components: olanzapine; a cocrystal former; water; solvent (isopropylacetate). To our knowledge this study is unprecedented in that the observed quaternary structures can be classified as solvates, hydrates, or cocrystals

Crystal Engineering of Isostructural Quaternary Multicomponent Crystal Forms of Olanzapine

Pharmaceutical cocrystals have gained increased attention at least in part because of their potential for enhancing physicochemical and biopharmaceutical properties of existing drugs. As a result, design, screening, and large-scale preparation of pharmaceutical cocrystals have been emphasized in recent research. The design of pharmaceutical cocrystals has focused primarily on determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach is typically less predictive when considering drugs that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. In this manuscript, we report a crystal engineering design strategy to facilitate the synthesis of multicomponent crystal forms of the atypical antipsychotic drug olanzapine, marketed as a drug product under the trade name Zyprexa. Comprehensive analysis and data mining of existing crystal structures of olanzapine were followed by grouping into categories according to the crystal packing exhibited and systematically using this information to crystal engineer new compositions. This approach afforded isostructural, quaternary multicomponent crystal forms of olanzapine composed of a stoichiometric ratio of four molecular components: olanzapine; a cocrystal former; water; solvent (isopropylacetate). To our knowledge this study is unprecedented in that the observed quaternary structures can be classified as solvates, hydrates, or cocrystals

Boosting Intracellular Delivery of Lipid Nanoparticle-Encapsulated mRNA

Intracellular delivery of mRNA holds great potential for vaccine− and therapeutic discovery and development. Despite increasing recognition of the utility of lipid-based nanoparticles (LNPs) for intracellular delivery of mRNA, particle engineering is hindered by insufficient understanding of endosomal escape, which is believed to be a main limiter of cytosolic availability and activity of the nucleic acid inside the cell. Using a series of CRISPR-based genetic perturbations of the lysosomal pathway, we have identified that late endosome/lysosome (LE/Ly) formation is essential for functional delivery of exogenously presented mRNA. Lysosomes provide a spatiotemporal hub to orchestrate mTOR signaling and are known to control cell proliferation, nutrient sensing, ribosomal biogenesis, and mRNA translation. Through modulation of the mTOR pathway we were able to enhance or inhibit LNP-mediated mRNA delivery. To further boost intracellular delivery of mRNA, we screened 212 bioactive lipid-like molecules that are either enriched in vesicular compartments or modulate cell signaling. Surprisingly, we have discovered that leukotriene-antagonists, clinically approved for treatment of asthma and other lung diseases, enhance intracellular mRNA delivery in vitro (over 3-fold, <i>p</i> < 0.005) and in vivo (over 2-fold, <i>p</i> < 0.005). Understanding LNP-mediated intracellular delivery will inspire the next generation of RNA therapeutics that have high potency and limited toxicity

Prodrugs of Pioglitazone for Extended-Release (XR) Injectable Formulations

<i>N-</i>Acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model candidates for extended-release injectable formulations. All PIO derivatives prepared are crystalline solids as determined by powder X-ray diffraction, and the solubility in aqueous media is below 1 μM at 37 °C. The melting points steadily increase from 55 °C, for the hexanoyloxymethyl derivative, to 85 °C, for the palmitoyloxymethyl derivative; inversely, the solubilities in ethyl oleate decrease as a function of increasing acyl chain length. The butyroyloxymethyl ester has a higher melting point and a lower solubility in ethyl oleate than expected from the trend. The ¹³C solid-state NMR spectra of the PIO homologues between the hexanoyloxymethyl derivative and stearoyloxymethyl derivative suggest a common structural motif with the acyl chains exchanging between two distinct conformations, and the rate of exchange is slower for longer chain derivatives. The butyroyloxymethyl derivative is efficiently converted to PIO in <i>in vitro</i> rat plasma with a half-life of <2 min at 37 ^o C, while the rate of enzymatic cleavage in rat plasma decreases as the ester chain length increases for the longer acyloxymethyl derivatives. The concentration of PIO in plasma increases rapidly, or “spikes,” in the hours following intramuscular (IM) injection of either the HCl salt or the butyroyloxymethyl derivative. In contrast, the more lipophilic palmitoyloxymethyl derivative provides slow growth in the PIO concentration over the first day to reach levels that remain steady for 2 weeks. On the basis of its <i>in vivo</i> pharmacokinetic profile, as well as material and solubility properties, the PIO palmitoyloxymethyl derivative has potential as a once-monthly injectable medication to treat diabetes