Pharmaceutical cocrystals

Cocrystal screening and single-crystal growth remain the primary obstacles in the development of pharmaceutical cocrystals. Here, we present a new approach for cocrystal screening, microspacing in-air sublimation (MAS), to obtain new cocrystals and grow high-quality single crystals of cocrystals within tens of minutes. The method possesses the advantages of strong designable ability of devices, user-friendly control, and compatibility with materials, especially for the thermolabile molecules. A novel drug-drug cocrystal of favipiravir (FPV) with salicylamide (SAA) was first discovered by this method, which shows improved physiochemical properties...

The present work aims to explore the new solid forms of telmisartan (TEL) with alpha-ketoglutaric acid (KGA) and glutamic acid (GA) as potential coformers using mechanochemical approach and their role in augmentation in physicochemical parameters over pure crystalline TEL. Mechanochemical synthesis was performed using 1:1 stoichiometric ratio of TEL and the selected coformers in the presence of catalytic amount of ethanol for 1 h. The ground product was characterized by PXRD, DSC, and FTIR. The new solid forms were evaluated for apparent solubility, intrinsic dissolution, and physical stability...

Antascomicin B is a natural product that similarly to the macrolides FK506 and Rapamycin binds to the FK506-binding protein 12 (FKBP12). FK506 and Rapamycin act as molecular glues by inducing ternary complexes between FKBPs and additional target proteins. Whether Antascomicin B can induce ternary complexes is unknown. Here we show that Antascomicin B binds tightly to larger human FKBP homologs. The cocrystal structure of FKBP51 in complex with Antascomicin B revealed that large parts of Antascomicin B are solvent-exposed and available to engage additional proteins...

The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure-activity relationship study that led to the discovery of compound 11 , a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor...

A novel one-pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral α, (α-diphenyl-2-pyrrolidinemethanol) formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)-enantiomer and (2S,3S)-enantiomer in solution, achieving a one-pot spontaneous deracemization.  This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)-carprofen, (R,S)-indoprofen, and (R,S)-indobufen...

In a typical tablet or capsule formulation, the active drug is often present as a crystalline solid. This solid emerges from the relationships between the individual atoms within the crystal, which confer a distinct set of physical properties. Thus, the packing arrangement of the individual drug molecules within these crystals can be modified by crystal engineering to modulate their properties. Crystal engineering has also seen teams arrange multiple drug molecules within the same crystal, which has resulted in dramatic improvements to drug properties in the lab...

The solid-state reaction of the active pharmaceutical ingredient theophylline with citric acid is a well-established example of a mechanochemical reaction, leading to a model pharmaceutical cocrystal. Here, classical force field molecular dynamics was employed to investigate the molecular mixing and structural distortion that take place on the mechanically driven indentation of a citric acid nanoparticle on a slab of crystalline theophylline. Through non-equilibrium molecular dynamics simulations, a 6 nm diameter nanoparticle of citric acid was introduced onto an open (001) surface of a theophylline crystal, varying both the angle of incidence of the nanoparticle between 15° and 90° and the indentation speed between 1 m s-1 and 16 m s-1 ...

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling. While HPK1 is considered as a promising target for cancer immunotherapy, no small-molecule HPK1 inhibitors have been approved for cancer treatment. Herein, we report the discovery of a series of new HPK1 inhibitors with a 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one scaffold. The most potent compound 9f inhibited HPK1 kinase activity with an IC50 of 0.32 nM in the time-resolved fluorescence resonance energy transfer (TR-FRET) assays, while displayed reasonable selectivity in a panel of 416 kinases...

The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3KαH1047R over PI3KαWT is crucial due to the role that PI3KαWT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3KαH1047R -selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3KαH1047R with high selectivity over PI3KαWT , resulting in the discovery of compound 17 ...

Cognitive functions are lost due to the rapid hydrolysis of acetylcholine including Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE). Marine algae-derived compounds were reported for their neuroprotective activities and hence they can be utilised for treating neurodegenerative ailments like Alzheimer's Disease and Parkinson's Disease which are due to the loss of cognitive functions. Major attention is currently paid to seaweeds due to their health benefits and high nutritional values. Sea weeds are of a rich sense of natural bioactive compounds which antioxidants, pharmaceutical compounds, flavonoids and alkaloids...

Cocrystallization assembles multicomponent crystals in defined ratios that are held together by intermolecular interactions. While cocrystals have seen extensive use in the pharmaceutical industry for solving issues with stability and solubility, extension to the field of energetic materials for improved properties has proven difficult. Predicting successful coformers remains a challenge for systems lacking well-understood synthons that promote reliable intermolecular assembly. Herein, an alternative method is investigated for altering energetic properties that operates in the absence of well-defined interactions by molecular doping...

Our previous studies have demonstrated that BML284 is a colchicine-site tubulin degradation agent. To improve its antiproliferative properties, 45 derivatives or analogs of BML284 were designed and synthesized based on the cocrystal structure of BML284 and tubulin. Among them, 5i was the most potent derivative, with IC50 values ranging from 0.02 to 0.05 μM against the five tested tumor cell lines. Structure-activity relationship studies verified that the N1 atom of the pyrimidine ring was the key functional group for its tubulin degradation ability...

Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography...

Leishmaniasis is a neglected parasitic tropical disease with numerous clinical manifestations. One of the causative agents of cutaneous leishmaniasis (CL) is Leishmania tropica (L. tropica) known for causing ulcerative lesions on the skin. The adverse effects of the recommended available drugs, such as amphotericin B and pentavalent antimonial, and the emergence of drug resistance in parasites, mean the search for new safe and effective anti-leishmanial agents is crucial. Miltefosine (MIL) was the first recommended oral medication, but its use is now limited because of the rapid emergence of resistance...

This study describes the discovery of a unique ionic cocrystal of the active pharmaceutical ingredient (API) ponatinib hydrochloride ( pon·HCl ), and characterization using single-crystal X-ray diffraction (SCXRD) and solid-state NMR (SSNMR) spectroscopy. Pon·HCl is a multicomponent crystal that features an unusual stoichiometry, with an asymmetric unit containing both monocations and dications of the ponatinib molecule, three water molecules, and three chloride ions. Structural features include (i) a charged imidazopyridazine moiety that forms a hydrogen bond between the ponatinib monocations and dications and (ii) a chloride ion that does not feature hydrogen bonds involving any organic moiety, instead being situated in a "square" arrangement with three water molecules...

Cocrystallization is an effective method for altering the tableting performance of crystals by modifying their mechanical properties. In this study, cocrystals of ligustrazine (LIG) with malonic acid (MA) and salicylic acid (SA) were investigated to better understand how modifying crystal structure can affect tableting properties. LIG suffered from overcompression at high pressures despite its high plasticity. Both LIG-MA and LIG-SA displayed lower plasticity than LIG, which was confirmed by both an in-die Heckel and energy framework analyses...

In a competitive coformer exchange reaction, a recent topic of interest in pharmaceutical research, the coformer in a pharmaceutical cocrystal is exchanged with another coformer that is expected to form a cocrystal that is more stable. There will be a competition between coformers to form the most stable product through the formation of hydrogen bonds. This will cause destabilization of the pharmaceutical products during processing or storage. Therefore, it is important to develop a mechanistic understanding of this transformation by monitoring each and every step of the reaction, employing a technique such as 1 H nuclear magnetic resonance (NMR)...

Evidence supports boosting nicotinamide adenine dinucleotide (NAD+ ) to counteract oxidative stress in aging and neurodegenerative disease. One approach is to enhance the activity of nicotinamide phosphoribosyltransferase (NAMPT). Novel NAMPT positive allosteric modulators (N-PAMs) were identified. A cocrystal structure confirmed N-PAM binding to the NAMPT rear channel. Early hit-to-lead efforts led to a 1.88-fold maximum increase in the level of NAD+ in human THP-1 cells. Select N-PAMs were assessed for mitigation of reactive oxygen species (ROS) in HT-22 neuronal cells subject to inflammatory stress using tumor necrosis factor alpha (TNFα)...

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign. Initially our inhibitors suffered from low selectivity vs MMP12...

The therapeutic potential of pharmaceutical cocrystals in intranasal applications remains largely unexplored despite progressive advancements in cocrystal research. We present the application of spray freeze drying (SFD) in successful fabrication of a favipiravir-pyridinecarboxamide cocrystal nasal powder formulation for potential treatment of broad-spectrum antiviral infections. Preliminary screening via mechanochemistry revealed that favipiravir (FAV) can cocrystallize with isonicotinamide (INA), but not nicotinamide (NCT) and picolinamide (PIC) notwithstanding their structural similarity...