Continuous manufacturing of co-crystals: challenges and prospects.

The last decade has witnessed extensive growth in the field of co-crystallization for mitigating the solubility and dissolution-related issues of poorly soluble drugs. This is largely because co-crystals can modify the physicochemical properties of drugs without any covalent modification in the drug molecules. The US Food and Drug Administration (FDA) now considers drug products that are designed to contain a new co-crystal, analogous to new polymorph of the active pharmaceutical ingredient (API). This positive change in regulatory perspective coupled with successful commercialization of valsartan-sacubitril co-crystal (Entresto, Novartis) has now brought co-crystals into focus, in both industries as well as academia. Co-crystal prediction, screening, and synthesis have been reported in literature; however, co-crystal production at a larger scale needs further investigations. With this aim, the article describes various continuous methods for co-crystal production, along with in-line monitoring during co-crystal production, emphasizing on process analytical technology (PAT). In addition, the scale-up issues of continuous and batch co-crystallization and other suitable techniques for pharmaceutical scale up are detailed. Quality control aspects and regulatory viewpoint crucial for commercial success are elaborated in the future perspective.

Rufinamide: Crystal structure elucidation and solid state characterization.

Rufinamide (R) is a triazole derivative approved for the management of partial seizures and seizures associated with Lennox-Gastaut Syndrome, in November 2007. Crystal structure, solid state characterization, drug-excipient compatibility and solubility play a pivotal role in formulation development. This work deals with the crystal structure elucidation of R by single crystal X-ray diffraction and solid state characterization by thermal, spectroscopic and crystallographic techniques. Drug- excipient compatibility was assessed by differential scanning calorimetry (DSC). New RP-HPLC method for quantification of R was developed with improved retention time. Solubility and dissolution of drug in different media was determined. Additionally, the flow behavior of the drug was evaluated by measuring Carr's index and Hausner's ratio, while the compressibility behavior was studied using Well's protocol. R crystallized from dimethylformamide (R-DMF) was utilized for single crystal analysis. The drug crystallized in triclinic crystal system with P-1 space group. Asymmetric unit cell consists of two molecules of R held by intermolecular hydrogen bond (connected by NH⋯O, which forms the catemeric chain). Analytical outcomes from DSC, thermogravimetric analysis (TGA) and powder X-ray diffraction (PXRD) revealed that the drug was present in pure crystalline form and was devoid of any polymorphic or pseudopolymorphic impurities. Influence of pH on the solubility and dissolution of R-DMF was found to be insignificant. The drug exhibited poor aqueous solubility, which was improved nearly 4.6 fold with the addition of 2% sodium lauryl sulphate (SLS). The drug exhibits poor flow and elastic compression nature. Excipients such as poly ethylene glycol (PEG) 8000, SLS, lactose monohydrate, starch and Hydroxypropyl methylcellulose (HPMC) E15 were incompatible with R-DMF as identified by thermal analysis. It is envisaged that these information regarding solid state properties of R-DMF would aid in identifying a logical path for formulation development.

Preparation, characterization, and cytotoxicity studies of niclosamide loaded mesoporous drug delivery systems.

Recent reports on the anticancer potential of niclosamide have opened new avenues for anticancer treatment. Niclosamide belongs to the BCS class II, which is indicative of poor solubility and dissolution rate limited absorption. The aim of this study was to improve the dissolution rate of the drug by mesoporous drug delivery system. Porous silica grades (ordered and nonordered) with different pore size, pore volume and surface area were used in the study. The drug was loaded on silica carriers by the solvent evaporation method and characterized by BET surface area analysis, SEM, P-XRD, DSC, and FTIR. A discriminatory dissolution medium was developed for performing the in vitro dissolution of niclosamide. In comparison to the plain drug, all silica based formulations showed improvement in the dissolution rate. Maximum enhancement in the dissolution rate was observed in 1:2 drug:carrier loading ratio when compared to 1:1 ratio. Different properties of mesoporous silica like structural geometry, pore size and microenvironment pH demonstrated a significant impact on drug release from the formulations. Cytotoxicity of the optimized mesoporous formulations of niclosamide was explored in HCT-116, HCT-15, NCI, MDA-MB-231 and A549 cancer cell lines. Nearly 3 fold and 2 fold increase in% cytotoxicity of drug loaded Syloid-244 and Sylysia 350 at 1:2 ratio respectively, were observed when compared to the plain drug.

Fast dissolving drug-drug eutectics with improved compressibility and synergistic effects.

Combinational therapy has become increasingly popular in recent times due to various advantages like greater therapeutic effect, reduced number of prescriptions, lower administrative costs, and an increase in patient compliance. Drug-drug multicomponent adducts could help in combination of drugs at supramolecular level. Two drug-drug eutectics of etodolac with paracetamol (EP) and etodolac with propranolol hydrochloride (EPHC) were successfully designed and synthesized for the first time. These eutectics significantly improved dissolution and material properties. A 6 to 9 fold enhancement in % dissolution efficiency was found at 1min suggesting the fast dissolving capabilities of the eutectic mixtures when compared to plain drug. In addition, eutectic mixtures have shown improved hardness compared to plain drugs. EP and EPHC have shown around 5 fold and 3 fold improvements in hardness respectively at 10MPa when compared to plain etodolac. Cell culture studies have shown improved effects of EP. Western blotting analysis revealed that the said combination successfully reduced various inflammatory mediators like TNF-α, COX-2 and IL-6. Whereas, the eutectic combination EPHC has shown enhanced cytotoxic effects with synergistic combination index and favorable dose reduction index. The generated multi-component systems EP and EPHC with fast dissolving capabilities, improved hardness at lower pressures and synergistic effects represent prospective combinations for effective treatment of osteoarthritis and cancer chemotherapy respectively.

Co amorphous systems: A product development perspective.

Solubility is one of the major problems associated with most of the new chemical entities that can be reasonably addressed by drug amorphization. However, being a high-energy form, it usually tends to re-crystallize, necessitating new formulation strategies to stabilize amorphous drugs. Polymeric amorphous solid dispersion (PASD) is one of the widely investigated strategies to stabilize amorphous drug, with major limitations like limited polymer solubility and hygroscopicity. Co amorphous system (CAM), a new entrant in amorphous arena is a promising alternative to PASD. CAMs are multi component single phase amorphous solid systems made up of two or more small molecules that may be a combination of drugs or drug and excipients. Excipients explored for CAM preparation include amino acids, carboxylic acids, nicotinamide and saccharine. Advantages offered by CAM include improved aqueous solubility and physical stability of amorphous drug, with a potential to improve therapeutic efficacy. This review attempts to address different aspects in the development of CAM as drug products. Criterion for co-former selection, various methods involved in CAM preparation, characterization tools, stability, scale up and regulatory requirements for the CAM product development are discussed.

Multidrug co-crystals: towards the development of effective therapeutic hybrids.

Co-crystals have garnered the interest of the pharmaceutical industry with the introduction of regulatory guidelines by the US Food and Drug Administration (FDA) as a result of expanded patent portfolios. The Phase II clinical success of tramadol and celecoxib co-crystal for the treatment of acute pain followed by a recent reflection paper published by the European Medicines Agency (EMA) have further boosted the development of drug-drug co-crystals. Here, we shed light on the developments of drug-drug co-crystals and highlight future perspectives for exploring new therapeutic hybrids deploying drug-drug, drug-nutraceuticals and drug-inorganic salt combinations with improved pharmaceutical and biopharmaceutical performance.

Micellar carriers for the delivery of multiple therapeutic agents.

Multi-drug therapy is described as a simultaneous or sequential administration of two or more drugs with similar or different mechanisms of action and is recognized as a more efficient solution to combat successfully, various ailments. Polymeric micelles (PMs) are self-assemblies of block copolymers providing numerous opportunities for drug delivery. To date various micellar formulations were studied for delivery of drugs, nutraceuticals and genes; a few of them are in clinical trials. It was observed that there is an immense need for the development of PMs embedding multiple therapeutic agents to combat various ailments, including cancers, HIV/AIDS, malaria, multiple sclerosis, hypertension, infectious diseases, cardiovascular and metabolic diseases, immune disorders and many psychiatric disorders. Several combinations of drug-drug, drug-nutraceutical, drug-gene and drug-siRNA explored to date are detailed in this review, with a special emphasis on their potential and future perspectives. A summary of various preparation methods, characterization techniques and applications of PMs are also provided. This review presents a holistic approach on multi-drug delivery using micellar carriers and emphasizes on the development of therapeutic hybrids embedding novel combinations for safer and effective therapy.

Can crystal engineering be as beneficial as micronisation and overcome its pitfalls?: A case study with cilostazol.

Improvement in dissolution of the drugs having poor solubility is a challenge in pharmaceutical industry. Micronization is one technique, employed for dissolution enhancement of cilostazol, a BCS class II drug. However, the obtained micronized drug possesses poor flowability. The aim of this study was to improve the dissolution rate and flow properties of cilostazol by crystal engineering, using habit modification method and compare with micronized cilostazol bulk drug. Simulation studies were performed to predict the effect of solvents on cilostazol crystal habit. Cilostazol crystals with different habits were prepared by solvent:anti-solvent crystallization technique. SEM, FTIR, DSC, TGA and PXRD were used for solid state characterization. The results revealed that cilostazol re-crystallized from methanol-hexane system were hexagonal and ethanol-hexane system gave rods. Cilostazol engineered habits showed increased dissolution rate than unprocessed drug but similar dissolution rate when compared to micronized cilostazol. Micronized cilostazol showed a dissolution efficiency of 75.58% where as cilostazol recrystallized from methanol-hexane and ethanol-hexane systems resulted in a dissolution efficiency of 72.63% and 68.63%, respectively. In addition, crystal engineering resulted in improved flow properties of re-crystallized habits when compared to micronized form of the drug. In conclusion, crystal engineering by habit modification show potential for dissolution enhancement with an added advantage of improved flow properties over micronization technique, for poorly soluble drugs like cilostazol.

Effect of meditation on neurophysiological changes in stress mediated depression.

Meditation is a complex mental practice involving changes in sensory perception, cognition, hormonal and autonomic activity. It is widely used in psychological and medical practices for stress management as well as stress mediated mental disorders like depression. A growing body of literature has shown that meditation has profound effects on numerous physiological systems that are involved in the pathophysiology of major depressive disorder (MDD). Although meditation-based interventions have been associated with improvement in depressive symptoms and prevention of relapse, the physiological mechanisms underlying the therapeutic effects of meditation are not clearly defined and even paradoxical. This paper reviews many of the physiological abnormalities found in cytokine & stress mediated depression and the reversal of these anomalies by different meditation techniques.

Eluting combination drugs from stents.

Cardiovascular diseases (CVD) are one of the leading causes of death across the globe. Pathogenesis of coronary artery disease (CAD) is lead by the progression of atherosclerotic lacerations in coronary arteries. Percutaneous coronary intervention (PCI) using balloon angioplasty was introduced in 1979 and was majorly used in the treatment of these lesions. Introduction of bare metal stents (BMS) has revolutionized stenting procedures overcoming elastic recoil and reducing restenosis commonly associated with balloon angioplasty, but follow up studies have shown 20-30% prevalence of in-stent restenosis (ISR), this led to the development of drug eluting stents (DES). But long-term follow up studies have shown increased liability of stent thrombosis. Boosting the development of safer and effective DES expounding for therapies like biodegradable polymer based DES, polymer free DES, bioresorbable DES and combination DES to collectively reduce neointimal hyperplasia and promote endothelial healing. In dual-DES development, a combination employing an anti-restenotic agent (for preventing VSMC's proliferation), which is released for the first few weeks, and then the second drug a pro-healing agent (promoting re-endothelialization) released after a month would be ideal. Growing understanding in the areas of polymer therapeutics, nanoscale surface modifications and gene therapy would assist in the delivery of multiple drugs, which would further help in the design of promising therapeutic strategies for the treatment of CAD using stent based therapies.