New Cocrystals of Antipsychotic Drug Aripiprazole: Decreasing the Dissolution through Cocrystallization.
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ABSTRACT:
SUBMITTER: Liu W
PROVIDER: S-EPMC8122301 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cocrystallization is a promising approach to alter physicochemical properties of active pharmaceutical ingredients (hereafter abbreviated as APIs) bearing poor profile. Nowadays pharmaceutical industries are focused on preparing drug-drug cocrystals of APIs that are often prescribed in combination therapies by physicians. Physicians normally prescribe antibiotic with an analgesic/antipyretic drug to combat several ailments in a better and more efficient way. In this work, azithromycin (AZT) and paracetamol (PCM) cocrystals were prepared in 1:1 molar ratio using slow solvent evaporation method. The cocrystals were characterized by Fourier transform infrared (FTIR), Raman spectroscopy, powder X-ray diffraction (PXRD), differential scanning calorimeter (DSC), thermo gravimetric analysis (TGA) and high-performance liquid chromatography (HPLC). Vibrational spectroscopy and DSC confirmed that both APIs interact physically and showed chemical compatibility, while PXRD pattern of the starting material and products revealed that cocrystal have in a unique crystalline phase. The degree of hydration was confirmed by TGA analysis and result indicates monohydrate cocrystal formation. The HPLC analysis confirmed equimolar ratio of AZT:PCM in the cocrystal. The in vitro dissolution rate, saturation solubility, and antimicrobial activity were evaluated for AZT dihydrate and the resulting cocrystals. The cocrystals exhibited better dissolution rate, solubility and enhanced biological activities.
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Project description:Purpose: To enhance the dissolution rate of the poorly soluble drug atorvastatin calcium (ATC) by cocrystallization with selected coformers. Enhancement of the dissolution rate and solubility of the drug, which is classified as Class II of the Biopharmaceutical Classification System (BCS), is expected to enhance the bioavailability. Methods: Two methods were used for preparing the cocrystals, solvent drop grinding (SDG) and solvent evaporation (SE) method using 1:1, 1:3, and 1:10 drug-coformer molar ratios. Glucosamine hydrochloride (GluN) and nicotinamide (NIC) were investigated as coformers. The cocrystals, their physical mixtures, and the raw ATC were characterized by fourier transform infrared (FTIR spectroscopy), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), mass spectroscopy (MS), scanning electron microscopy (SEM), solubility, and dissolution rate studies. Results: SDG and SE were effective in improving the dissolution rate of ATC with both coformers. Drug: coformer ratio 1:3 was optimum. The solubility values for ATC, GluN-, and NIC-cocrystals were 26, to 35 and 50 µg/mL, respectively. The dissolution rate of ATC from cocrystals was > 90% after 5 minutes, compared to 41% untreated ATC. Conclusion: Cocrystallization significantly improved the solubility and dissolution, in comparison to the untreated ATC.
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Project description:Weakly basic drugs are predisposed to order of magnitude decreases in solubility and dissolution as pH increases from 1 to 7 along the gastrointestinal tract. Such behavior is known to be detrimental to drug absorption. The work presented here shows how cocrystals of basic drugs with acidic coformers can mitigate these negative effects. Cocrystals of ketoconazole (KTZ) with adipic, fumaric, and succinic acids exhibit a parabolic solubility dependence on pH such that with increasing pH, solubility decreases, reaches a minimum, and increases. Cocrystals exhibit pHmax values between 3.6 and 3.8, above which they generate supersaturation with respect to drug. Cocrystal supersaturation index (SA), defined as Scocrystal/Sdrug, changes from 1 (pHmax) to 10-30 (pH 5) to 800 - 3,000 (pH 6.5). SA represents the driving force for cocrystal conversion to the less soluble drug during dissolution. SA is not expected to be equal to the observed supersaturation, but it is of great value to classify cocrystals in terms of their risk of conversion. Cocrystal dissolution behavior was analyzed in terms of Cmax, ?max (maximum KTZ concentration and supersaturation), AUCdiss (KTZ concentration area under the curve during dissolution-precipitation), and SA. The three cocrystals studied achieved ?max values between 5 and 15 and sustained supersaturation for 1 to 3 h, resulting in AUCdiss advantage over drug in the range of 2 to 12. SA values as high as 800 were associated with enhanced drug exposure. SA of 3,000 led to limited exposure, very rapid conversion, and no measurable supersaturation. Since cocrystals may be more soluble than needed and/or too soluble to be developed, there is great value in recognizing the relationship between supersaturation threshold, cocrystal solubility, and SA. This becomes more important as cocrystal SA is dependent on pH and other environmental conditions.
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Project description:Muscle relaxant and pain reliever metaxalone (MET) is a biopharmaceutical classification systems (BCS) class II drug with poor aqueous solubility and high permeability. The presence of an aromatic skeleton and cyclic carboxamate moiety are the probable reasons for the decreased aqueous solubility, which impacts on its low bioavailability. A high dose (800 mg) of the drug often creates adverse side effects on the central nervous system that needs urgent remedy. Cocrystallization of MET with nicotinamide (NAM), salicylamide (SAM), and 4-hydroxybenzoic acid (HBA) resulted in multicomponent solids that were characterized by PXRD, DSC and single crystal X-ray diffraction. Cocrystals with SAM and NAM form 2D isostructural cocrystals, whereas with HBA the result is a differently packed cocrystal hydrate (or anisole hemisolvate) depending upon the crystallization medium. Similar to the reported MET cocrystals, these cocrystals also confirm the preference for an imide⋯imide homosynthon in the drug. The dominance of the drug-drug homodimer over drug-coformer heterodimers was demonstrated based on binding energy calculations. Further, powder dissolution experiments in pH 6.8 phosphate buffer indicate that the cocrystals improved the apparent solubility compared to the native drug by 3-9 fold. The absence of stronger heterosynthons between MET and the coformers, their lower melting points and the high solubility of the coformers are the probable reasons for the enhanced solubility of the bioactive component. The MET-NAM cocrystal exhibited the highest solubility/dissolution rate among the three binary solid forms, which may offer improved bioavailability and a lower dose with minimal side effects.
| S-EPMC9041148 | biostudies-literature
Project description:In this work, we are the first to identify thirteen cocrystals of Nefiracetam, a poor water-soluble nootropic compound. Three of which were obtained with the biocompatible cocrystallization agents citric acid, oxalic acid, and zinc chloride. These latter have been fully structurally and physically characterized and the solubility, dissolution rate, and stability were compared to that of the initial Active Pharmaceutical Ingredient (API).
| S-EPMC7408141 | biostudies-literature
Project description:Improving dissolution properties of active pharmaceutical ingredients (APIs) is a critical step in drug development with the increasing occurrence of sparingly soluble APIs. Cocrystal formation is one of the methods to alter the physicochemical properties of APIs, but its dissolution behavior in biorelevant media has been scrutinized only in recent years. We investigated the combined strategy of cocrystallization and eutectic formation in this regard and utilized the cocrystal model system of naproxen and three pyridinecarboxamide isomers. Binary melting diagrams were constructed to discover the eutectic compositions of the three cocrystals with excess amounts of pyridinecarboxamides. The melt-crystallized eutectics and cocrystals were compared in their dissolution behaviors with respect to neat naproxen. The eutectics enhanced the early dissolution rates of the cocrystals in both the absence and presence of biologically relevant bile salt and phospholipid components, whereas the cocrystal dissolution was expedited and delayed, respectively. The combined strategy in the present study will be advantageous in maximizing the utility of the pharmaceutical cocrystals.
| S-EPMC8145234 | biostudies-literature
Project description:BACKGROUND:Aripiprazole is a relatively new antipsychotic drug, said to be the prototype of a new third generation of antipsychotics; the so-called dopamine-serotonin system stabilisers. In this review we examine how the efficacy and tolerability of aripiprazole differs from that of typical antipsychotics. OBJECTIVES:To evaluate the effects of aripiprazole compared with other typical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY:We searched the Cochrane Schizophrenia Group Trials Register (November 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies for further trials. We contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. SELECTION CRITERIA:We included all randomised trials comparing aripiprazole with typical antipsychotics in people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS:We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model. We have contacted representatives of Bristol Myers Squibb pharmaceuticals (UK) for additional data. MAIN RESULTS:We included nine randomised trials involving 3122 people comparing aripiprazole with typical antipsychotic drugs. None of the studies reported on relapse - our primary outcome of interest. Attrition from studies was high and data reporting poor. Participants given aripiprazole were comparable to those receiving typical drugs in improving global state and mental state. Aripiprazole provided a significant advantage over typical antipsychotics in terms of fewer occurrences of extra-pyramidal symptom (n=968, 3 RCT, RR 0.46 CI 0.3 to 0.9, NNT 13 CI 17 to 10), and particularly akathisia (n=897, 3 RCT, RR 0.39 CI 0.3 to 0.6, NNT 11 CI 14 to 9). Fewer participants given aripiprazole developed hyperprolactinaemia (n=300, 1 RCT, RR 0.07 CI 0.03 to 0.2, NNT 2 CI 3 to 1). Aripiprazole presented a lesser risk of sinus tachycardia (n=289, 1 RCT, RR 0.09 CI 0.01 to 0.8, NNT 22 CI 63 to 13) and blurred vision (n=308, 1 RCT, RR 0.19 CI 0.1 to 0.7, NNT 14 CI 25 to 10); but enhanced risk of occurrence of dizziness (n=957, 3 RCT, RR 1.88 CI 1.1 to 3.2, NNH 20 CI 33 to 14) and nausea (n=957, 3 RCT, RR 3.03 CI 1.5 to 6.1, NNH 17 CI 25 to 13). Attrition rates were high in both groups, although significantly more participants in the aripiprazole group completed the study in the long term (n=1294, 1 RCT, RR 0.81 CI 0.8 to 0.9 NNT 8 CI 5 to 14). AUTHORS' CONCLUSIONS:Aripiprazole differs little from typical antipsychotic drugs with respect to efficacy, however it presents significant advantages in terms of tolerability. Clearly reported pragmatic short, medium and long term randomised controlled trials are required to replicate and validate these findings and determine the position of aripiprazole in everyday clinical practice.
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Project description:Aripiprazole is an atypical antipsychotic drug approved for the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and autism. The drug shows partial agonistic activity at dopamine D(2) receptors and 5-hydroxytryptamine (5-HT) 5-HT(1A) receptors, and antagonistic activity at 5-HT(2A) receptors. However, the precise mechanistic pathways remain unclear. In this study, we examined the effects of aripiprazole on neurite outgrowth. Aripiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. The 5-HT(1A) receptor antagonist WAY-100635, but not the dopamine D(2) receptor antagonist sulpiride, blocked the effects of aripiprazole, although, only partially. Specific inhibitors of inositol 1,4,5-triphosphate (IP(3)) receptors and BAPTA-AM, a chelator of intracellular Ca(2+), blocked the effects of aripiprazole. Moreover, specific inhibitors of several common signaling pathways phospholipase C-γ (PLC-γ), phosphatidylinositol-3 kinase (PI3K), mammalian target of rapamycin, p38 MAPK, c-Jun N-terminal kinase, Akt, Ras, Raf, ERK, MAPK) also blocked the effects of aripiprazole. Using proteomic analysis, we found that aripiprazole significantly increased levels of the heat shock protein Hsp90α in cultured cells. The effects of aripiprazole on NGF-induced neurite outgrowth were significantly attenuated by treatment with Hsp90α RNA interference, but not by the negative control of Hsp90α. These findings suggest that both 5-HT(1A) receptor activation and Ca(2+) signaling via IP(3) receptors, as well as their downstream cellular signaling pathways play a role in the promotion of aripiprazole-induced neurite outgrowth. Furthermore, aripiprazole-induced increases in Hsp90α protein expression may form part of the therapeutic mechanism for this drug.
| S-EPMC3565827 | biostudies-literature
Project description:The effect of hydroxypropyl methylcellulose (HPMC) and methylcellulose (Methocel® 60 HG) on the dissolution behavior of two cocrystals derived from nitazoxanide (NTZ), viz., nitazoxanide-glutaric acid (NTZ-GLU, 1:1) and nitazoxanide-succinic acid (NTZ-SUC, 2:1), was explored. Powder dissolution experiments under non-sink conditions showed similar dissolution profiles for the cocrystals and pure NTZ. However, pre-dissolved cellulosic polymer in the phosphate dissolution medium (pH 7.5) modified the dissolution profile of NTZ when starting from the cocrystals, achieving transient drug supersaturation. Subsequent dissolution studies under sink conditions of polymer-based pharmaceutical powder formulations with NTZ-SUC cocrystals gave a significant improvement of the apparent solubility of NTZ when compared with analogous formulations of pure NTZ and the physical mixture of NTZ and SUC. Scanning electron microscopy and powder X-ray diffraction analysis of samples recovered after the powder dissolution studies showed that the cocrystals undergo fast dissolution, drug supersaturation and precipitation both in the absence and presence of polymer, suggesting that the solubilization enhancement is due to polymer-induced delay of nucleation and crystal growth of the less soluble NTZ form. The study demonstrates that the incorporation of an appropriate excipient in adequate concentration can be a key factor for inducing and maintaining the solubilization of poorly soluble drugs starting from co-crystallized solid forms. In such a way, cocrystals can be suitable for the development of solid dosage forms with improved bioavailability and efficacy in the treatment of important parasitic and viral diseases, among others.
| S-EPMC7022799 | biostudies-literature
Project description:It is impossible to optimize a process for a target drug product with the desired profile without a proper understanding of the interplay among the material attributes, the process parameters, and the attributes of the drug product. There is a particular need to bridge the micro- and mesoscale events that occur during this process. Here, we propose а molecular engineering methodology for the continuous cocrystallization process, based on Raman spectra measured experimentally with a probe and from quantum mechanical calculations. Using molecular dynamics simulations, the theoretical Raman spectra were calculated from first principles for local mixture structures under an external shear force at various temperatures. A proof of concept is developed to build the process design space from the computed data. We show that the determined process design space provides valuable insight for optimizing the cocrystallization process at the nanoscale, where experimental measurements are difficult and/or inapplicable. The results suggest that our method may be used to target cocrystallization processes at the molecular scale for improved pharmaceutical synthesis.
| S-EPMC9173768 | biostudies-literature