New Chemical Entities Research Articles

Expedition to Phenanthrene Nucleus: A Two‐decade Research on Bench

AbstractThe phenanthrene nucleus is extensively found in diverse natural products and its versatility is not just limited to pharmaceutically beneficial molecules but has proved efficient in the development and synthesis of dyes, plastics, pesticides and explosives. Such a relevant nucleus has attracted researchers to probe into the construction of phenanthrene nucleus. The past two decades have witnessed continuous efforts in this direction with the exploration of various synthetic strategies enabling access to the privileged core. The review focuses on bringing the advances made in 20 years in these synthetic protocols and the mechanism involved in the generation of phenanthrene and its derivatives under one roof. In addition, it also provides a comparative study of the diverse approaches and vivid reactions employed for phenanthrene synthesis providing a better understanding and creating newer ideas towards the development of new chemical entities (NCEs).

The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.

We characterized the size of the premarket safety population for 278 small-molecule new molecular entities (NMEs) and 61 new therapeutic biologics (NTBs) approved by the US Food and Drug Administration (FDA) between October 1, 2002, and December 31, 2014, evaluating the relationship of premarket safety population size to regulatory characteristics and postmarket safety outcomes. The median size of the safety population was 1,044, and was lower for NTBs than NMEs (median: 920 vs. 1,138, P=0.04), orphan products than nonorphan products (393 vs. 1,606, P<0.001), and for products with fast-track designation (617 vs. 1,455, P<0.001), priority review (630 vs. 1,735, P<0.001), and accelerated approval (475 vs. 1,164, P<0.001), than products without that designation. The median number of postmarket safety label updates and issues added to the label were higher with larger premarket exposure among nonorphan products, but not among orphan products. Products with accelerated approval using a surrogate end point had a higher median number of safety issues added to the label than those with full approval, but this did not vary with the size of the safety population; fast-track and priority review were not associated with the number of safety issues added to the label. A smaller safety population size was associated with a longer time to first safety outcome for nonorphan products but not orphan products. For orphan and nonorphan products combined, smaller premarket safety population size is not associated with the number or timing of postmarket safety outcomes, regardless of expedited program participation.

Systematic risk identification and assessment using a new risk map in pharmaceutical R&D

Delivering transformative therapies to patients while maintaining growth in the pharmaceutical industry requires an efficient use of research and development (R&D) resources and technologies to develop high-impact new molecular entities (NMEs). However, increasing global R&D competition in the pharmaceutical industry, growing impact of generics and biosimilars, more stringent regulatory requirements, as well as cost-constrained reimbursement frameworks challenge current business models of leading pharmaceutical companies. Big data-based analytics and artificial intelligence (AI) approaches have disrupted various industries and are having an increasing impact in the biopharmaceutical industry, with the promise to improve and accelerate biopharmaceutical R&D processes. Here, we systematically analyze, identify, assess, and categorize key risks across the drug discovery and development value chain using a new risk map approach, providing a comprehensive risk–reward analysis for pharmaceutical R&D.

FDA Analysis of Racial Demographics in Multiple Myeloma Trials

IntroductionMultiple Myeloma (MM) is a clonal plasma cell neoplasm characterized by end organ damage or derangement of highly specific biomarkers. The incidence of MM in the United States (U.S.) is estimated to be 30,280 new cases per year, accounting for approximately 1 percent of all cancers and 12,590 deaths per year.(1) The median age of diagnosis of MM has been reported as 66 years in the literature.(2) The incidence of MM is two to three times higher in black individuals than in whites, but the biological etiology of the observed higher incidence is undetermined. Blacks constitute 20% of the population affected by MM despite accounting for 13% of the U.S. population.(3,4) This disparity is also observed in the precursor condition, monoclonal gammopathy of undetermined significance (MGUS). Here we analyze the racial makeup of the pivotal trials submitted to the U.S. Food and Drug Administration (FDA) in support of MM indications with comparisons to the U.S. MM population.MethodsWe reviewed internal databases for NDA and BLA submissions to the FDA's Division of Hematology Products between 2003 and 2017. The pivotal trials supporting each application were reviewed for baseline demographic data, including age, race, and country. The clinical reviews, prescribing information, and clinical study reports were also reviewed. Intention-to-treat populations were examined. Analysis was conducted only on pivotal trials that included race data.ResultsWe found 21 original or supplemental NDAs or BLAs submitted between 2003 and 2017 in support of MM indications. The applications included 23 pivotal trials that were relied upon to support approval. Of these, 20 included race data. The median ages in each pivotal study ranged from 58 to 73 years, with a median age across trials of 64 years. The range of enrollment of black subjects in the pivotal trials was 0.5% to 19.9% of the trial population. The median percentage of blacks enrolled across the trials was 4.5%. The figure below shows the proportion of black subjects enrolled by trial. The enrollment of U.S. subjects in pivotal trials varied widely, with a median of 9.3% across trials. No chronologic trend was evident in U.S. enrollment, but U.S. participation was higher for new molecular entity (NME) pivotal trials as compared with supplemental applications. We found an association between U.S. enrollment and racial representation in clinical trials. In trials that had low U.S. enrollment, the median proportion of blacks enrolled was 1.8%, whereas in trials that had high U.S. enrollment, the median was 10.5%.DiscussionIn trials submitted in support of MM indications, the median percentage of blacks enrolled was 4.5%. SEER data from 2014 suggest that blacks represent 20% of the MM population. Based on these findings, enrollment of black subjects in pivotal trials submitted for U.S. regulatory approval is not representative of the population affected by MM. Even in trials that had high U.S. enrollment, black subject enrollment was not representative of the population affected by this disease. Underrepresentation of black patients in pivotal trials could be due to a number of factors, including access to care, and referral patterns to study enrollment sites.Meaningful differences may exist in MM disease biology, presentation, and response to treatment in blacks compared to whites.(5) Higher enrollment of black subjects in clinical trials would have multiple benefits. First, underserved populations would have improved access to novel therapies. Second, pivotal trials would be more representative of the U.S. population, which is a consideration within the regulatory benefit-risk framework. Finally, the additional data would provide further understanding of the MM disease biology in black patients, and potentially identify molecular subtypes that could be targeted by established or novel drugs.

EM1 When Are Breakthrough Therapies Cost-Effective?

The US Food and Drug Administration (FDA)-designated breakthrough therapies offer substantial potential to improve health outcomes, but it is unclear whether their health gains represent favorable value for money. Using the Tufts Medical Center Cost-Effectiveness (CE) Analysis Registry we: (1) summarized the cost-effectiveness of breakthrough therapies (BT), as measured by the cost-per-quality-adjusted-life-year (QALY) metric; (2) compared the cost-effectiveness of BT and non-breakthrough therapies (NBT) in the US; and (3) identified factors associated with BT cost-effectiveness, using logistic regression models with a range of value benchmarks ($50K-$150K/QALY). Between 2013 and 2018, FDA approved 264 drugs, designating 84 (32%) as breakthrough therapies. We identified published US CE studies for 26% of BT drugs (48 studies, 227 CE ratios) and 23% of NBT drugs (60 studies, 96 CE ratios). Publications focused on hepatitis C (HepC) or other infectious diseases (38% of BT studies, 23% of NBT studies) and neoplasms (48% of BT studies, 11% of NBT studies). Median BT incremental costs and QALYs exceeded corresponding values for NBT ($29,231 vs. $20,263 and 0.7 vs. 0.2 QALYs, respectively), and CE ratios trended toward greater favorability for BT compared to NBT drugs (median values $38,000/QALY vs. $50,000/QALY, respectively). For BTs, HepC drugs had the most favorable CE ratios, as removing HepC studies increased the median CE ratio to more than $140,000 (with median $65,000 incremental cost and 0.61 QALYs gained). Further, BTs for new molecular entities (NME) had median CE ratios about 40% lower than non-NME BTs, reflecting their smaller incremental costs and greater QALY gains. Breakthrough drugs may confer greater health benefits than NBTs in terms of QALYs gained. However, nuances, such as target condition, NME, and choice of comparator greatly influence whether greater relative health gains represent favorable value for money.

PDG37 Reporting of Patient-Reported Outcomes for Psoriasis in FDA Drug Labels, Medical Reviews, and Trial Publications: 2006-2019

Psoriasis is an autoimmune skin disease affecting patients’ daily lives significantly. To incorporate patient perspectives, patient-reported outcomes (PROs) have been widely used for treatment decision-making in patients with psoriasis. However, it is unclear whether the PROs are consistently reported in different drug information sources. This study examined the PRO data reporting in psoriasis drugs’ pivotal trials by comparing Food and Drug Administration (FDA) labeling, FDA medical reviews, and trial publications. We included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved by the FDA for psoriasis and/or psoriatic arthritis between 1/1/2006 and 12/31/2019. Product labeling and medical reviews of included drugs were collected from [email protected] (the FDA-approved drugs database) and examined details on PRO measures used in pivotal trials and the trials’ design. Using the identified trial design, trial registrations at ClinicalTrials.gov (the National Library of Medicine’s trial registry) were searched, and the list of publications was obtained. From the list, we identified matching trial publications by excluding review articles and duplicates, and the reporting of PRO measures were investigated. Data were extracted by two authors independently, and discrepancies were resolved through discussion. Of nine drugs indicated for psoriasis and/or psoriatic arthritis, seven (78%) of their product labeling contained information about five unique PRO measures. However, all of their FDA medical reviews included information about 14 unique PRO measures used in 21 pivotal trials. From ClinicalTrials.gov, 53 matching trial publications were identified, and 34 (64%) contained information about 13 unique PRO measures. Five drugs had discrepancies in reported PRO measures between FDA medical reviews and trial publications. PRO measures were inconsistently reported in psoriasis drugs’ product labeling, FDA medical reviews, and trial publications. Further investigation is warranted to explore the reasons behind such an inconsistent reporting of PRO measures among different drug information sources.

Developability profile framework for lead candidate selection in topical dermatology

The development of molecules for topical dermatology has primarily relied on drug repurposing or on combination therapies, leading to an average of only one New Chemical Entity (NCE) approved per year by the FDA. Topical products offer benefits to patients by enabling localized treatment, while minimizing systemic exposure and the likelihood of adverse events. New therapies are further justified by the burden skin diseases cause on patients’ quality of life. Notwithstanding the opportunities, the selection of a topical NCE presents challenges, primarily derived from a target product profile uncommon to oral drugs. Beyond a more stringent range of physicochemical properties, the molecule must display adequate solubility and chemical stability in topical-relevant excipients; must effectively cross the stratum corneum, considerably less permeable than the intestinal epithelium, and elicit a local therapeutic response; and must enable a formulation with robust physical stability. A novel framework intended to de-risk NCE selection is presented and based on four calculated physicochemical properties: molecular weight, clogP, topological polar surface area, and aromatic ring count. The use of topical-relevant solvents to assess the molecule’s solubility profile, and a 2-day accelerated chemical stability methodology, are also described as critical steps in early dermal development.

Biennial Analysis of Medication Guide Length and EstimatedReadability for New Molecular Entity Drugs, 2011-2017.

A medication guide (MG) is a form of FDA-approved labeling that provides patients with information about certain prescribed drugs so that patients can use these drugs safely and effectively. Given ongoing efforts by FDA and industry to continuously improve MG content and format, we hypothesized that more recently approved MGs for new molecular entities (NMEs) would be shorter and more readable compared to NME MGs approved earlier. We analyzed 53 NME MGs that were either approved in 2011 (n = 16), 2013 (n = 9), 2015 (n = 12), or 2017 (n = 16) to determine whether MG page length, word count, and readability scoresdiffered by year. Readability was estimated by Flesch Reading Ease, Flesch-Kincaid Grade Level (FKGL), Fry graph (FRY), and Gunning's Fog Index (FOG) scores. Mean page length was significantly lower in 2017 than in 2011 and 2013 (ps < .0001). Mean FKGL scores reflected sentences and words found in 8th grade textbooks, but mean FOG and FRY scores were consistent with sentences and words found in 10th and 11th grade textbooks. Although more recent NME MGs were shorter than older NME MGs, additional research is warranted to determine whether shorter MGs lead to improved readability. Developers choosing to estimate MG readability with equations should consider using multiple readability formulas and weigh the strengths and weaknesses of this approach. Using validated tools to more comprehensively assess MG readability should also be considered.

The drug lag issue: a 20-year review of China.

China has been criticized for the long drug delay for a long time. There was little understanding of Chinese drug lag formation from the investigational new drug (IND) submission to the new drug application (NDA) approval. Therefore, we analyzed the problem of drug lag in China cumulating from the clinical trial starting lag to the lags formed during the regulatory process and discerned the key underlying factors. After investigating the availability in China of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) between 1999 and 2019, we find that even though cutting regulatory process could reduce the approval lag, the clinical trial starting time in China is more important in drug lag reduction than shortening development time and review time. The reduction of the regulatory process also needs continuous efforts by defining the clinical value based on the medical needs, regulatory procedure harmonization, and intensive discussions between applicants and regulators during the drug development process. Meanwhile, proactive approaches should be taken to encourage developing the first generics in China. More importantly, enhancing domestic research and development capabilities is still the key to cutting the drug lag. Moreover, the China National Medical Product Administration (NMPA) should attach importance to the accumulation of regulation experience on innovative drugs and transform the style of regulating generics to new drugs.

Patient-reported outcomes in breast cancer FDA drug labels and review documents

BackgroundPatient-reported outcomes (PROs) can provide valuable information about drug benefit-risk tradeoffs from the patient perspective and are particularly important to patients with breast cancer due to its symptoms and adverse events from breast cancer treatments. The United States Food and Drug Administration (U.S. FDA) has acknowledged PROs as important approval endpoints used in clinical trials of cancer drugs. However, previous studies found that PROs are rarely mentioned in cancer drug labels, a widely used and trusted source of information about drugs. Our objectives were to compare PRO data reported in FDA labeling versus FDA medical review documents for breast cancer drugs approved in the U.S. between 2000 and 2019 to identify possible causes for PRO-data labeling exclusions.MethodsWe included new molecular entities (NMEs) and biologic license applications (BLAs) initially approved for breast cancer treatment by the FDA between 1/1/2000 and 12/31/2019. Product labeling and FDA medical review documents were collected from the FDA-Approved Drugs database (Drugs@FDA). From these resources, details on PRO measures used in trials, design of trials using PRO measures, PRO-endpoint status, analytical methods, and FDA reviewer comments regarding PRO measurement were extracted.ResultsOf 633 FDA-approved drugs, 13 were indicated for breast cancer treatment; none of their prescribing information contained information about PROs. However, 11 of 13 (85%) included PRO measures and endpoint information in FDA medical review documents. PRO measures were used in 14 different clinical trials, and FDA reviewers’ comments regarding PRO measurement were related to lack of meaningfulness and clinical significance, lack of content validity, and inadequate analytical methods.ConclusionsDespite the importance of PROs to patients with breast cancer, PRO measures were only described in FDA medical review documents of breast cancer drugs, but not in drug product labeling. Therefore, it appears that PRO data are often collected in breast cancer trials, but have not been methodologically acceptable to FDA reviewers. Collaborative efforts between the FDA and industry are warranted to increase the number of breast cancer drug applications with appropriate use of PRO measures and endpoints.

Opinion on the Use of Animal Models in Nonclinical Safety Assessment: Pros and Cons.

Nonclinical evaluation of human safety risks for new chemical entities (NCEs) is primarily conducted in conventional healthy animals (CHAs); however, in certain instances, animal models of diseases (AMDs) can play a critical role in the understanding of human health risks. Animal models of diseases may be especially important when there is a need to understand how disease conditions associated with the intended indication might impact risk assessment of NCEs or when CHAs lack the human-specific target of interest (receptor, etc). Although AMDs have potential benefits over CHAs, they also have limitations. Understanding these limitations and optimizing the AMDs of interest should be done prior to proceeding with studies that will guide development of NCE. The purpose of this manuscript is to provide an overview of the major pros and cons of utilization of AMDs in nonclinical safety assessment.

Synthetic Approaches to the New Drugs Approved during 2019

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.

Synthesis, biological evaluation, and molecular docking study of some new rohitukine analogs as protein tyrosine phosphatase 1B inhibitors

Rohitukine (RH) was extracted from the stem bark of Dysoxylum binectariferum Hook. It was derivatized to different arylsulphanmides by treating with the corresponding aryl sulphonyl chlorides. These derivatives were tested in-vitro on protein tyrosine phosphatase 1B (PTP1B) inhibition. Among these the active compounds K2, K3, K5, and K8 significantly inhibited the PTP1B by 51.3%, 65.6%, 71.9%, and 55.9% respectively at 10 µg/ml, the results were also supported by in-silico docking experiments. The most potent compound K5 was analyzed for antidiabetic and antidyslipidemic activity in vivo. It showed a marked reduction in blood glucose level (random and fasting) and serum insulin level in db/db mice. It improved glucose intolerance as ascertained by the oral glucose tolerance test (OGTT). These NCEs (New Chemical Entities) also lowered cholesterol and triglyceride profiles while improved high-density lipoprotein cholesterol in db/db mice. The K5 was further evaluated for antiadipogenic activity on MDI (Methylisobutylxanthine, dexamethasone, and insulin)-induced adipogenesis. where it significantly inhibited MDI-induced adipogenesis in 3 T3-L1 preadipocytes, at 10 µM and 20 µM concentration. These results were compared with the parent compound RH which inhibited 35% and 45% lipid accumulation while the RH analog K5 inhibited the lipid accumulation by 41% and 51% at 10 and 20 µM concentration, respectively. These results well corroborated with in-silico studies.

A Review on the Synthetic Approach of Marinopyrroles: A Natural Antitumor Agent from the Ocean

Natural products play an important role in various drug discovery and development approaches. They are known to be the rich resources for the identification of new chemical entities (NCEs) intended to treat various diseases. Many drugs have been discovered and developed from natural sources. Indeed, collaborative efforts involving biologists as well as organic, medicinal, and phytochemists usually facilitate the identification of potent NCEs derived from natural sources. Over the past 20 years, more than 50% of NCEs have been derived either from marine sources or synthetic/ semisynthetic derivatives of natural products. Indeed, many drug molecules have been designed by considering natural products as the starting scaffold. The first bis-pyrrole alkaloid derivative of marinopyrroles was obtained from the marine-derived streptomycete species. In the laboratory, it can be synthesized via Clauson-Kaas and Friedel-Crafts arylation as well as copper-mediated N-arylation process under microwave irradiation. The marinopyrrole A (±)-28 was discovered to overcome resistance against human cancer cells by antagonizing B-cell lymphoma extra-large (Bcl-xL) and induced myeloid leukaemia cell (Mcl-1). In this review, we elaborated on various synthetic pathways of marinopyrroles possessing anti-cancer potential, which could encourage researchers to discover promising anti-tumor agents.

Insights into Newly Approved Drugs from a Medicinal Chemistry Perspective.

The development of new drugs is becoming notably harder each decade. To overcome the present pitfalls in the drug development pipeline, such as those related to potency, selectivity, or absorption, distribution, metabolism, excretion and toxicity properties, medicinal chemistry strategies need to be in continuous evolution and need to become even more multidisciplinary. In this review, we present how structure-based, ligand-based, and fragment-based drug design (SBDD, LBDD, and FBDD, respectively) and their respective techniques were used for the design and optimization of successful cases of New Molecular Entities (NMEs) approved by the Food and Drug Administration (FDA).

Characterization and Applications of Colloidal Systems as Versatile Drug Delivery Carriers for Parenteral Formulations.

Preparing a suitable formulation for parenteral administration is already a difficult task; this, coupled with poor water-soluble new chemical entity (NCE), complicates this situation even further. There are several methodologies available to enhance water solubility, but this alone does not entail successful formulation. Making a micro/nano emulsion with a suitable surfactant not only increases the drug solubility but also the cell membrane permeability. Thus, not only biopharmaceutic classification system (BCS)-II (low solubility compounds) but also BCS-III (low permeability) and BCS-IV drugs (low solubility and low permeability) can be further exploited. Those drug candidates otherwise will not move further in NCE evaluation or clinical trials. This succinct review article delves into various aspects of biphasic micro/nano emulsion systems for parenteral drug delivery including the structure of the biphasic colloidal systems, characterization parameters, stability issues, regulatory considerations, and applications in life sciences.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Acknowledgment Letters and Filing Communications.

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA.

Molecular dynamics of hERG channel: insights into understanding the binding of small molecules for detuning cardiotoxicity

Evaluation of cardiotoxicity potential of new chemical entities (NCEs) has lately become one of the stringent filters in the drug discovery and development process. Cardiotoxicity is caused mainly by the inhibition of human ether-a-go-go related gene (hERG) channel protein. Inhibition of the hERG channel leads to a life-threatening condition known as cardiac arrhythmia. Knowledge of the structural behaviour of the hERG would aid greatly in the design of new drug molecules that do not interact with the protein and add to the safety index. In this study, a computational model for the active-state of hERG was developed. This model was equilibrated by performing the molecular dynamics simulations for 100 ns followed by clustering and selection of a representative structure based on the largest populated cluster. To study the changes in the protein structure on inhibition, three inhibitory ligands, namely, dofetilide, cisapride and terfenadine were docked, followed by molecular dynamics simulations of 200 ns for the apo and each ligand-bound structure. It was observed that docking and simulation studies of the hERG model exhibited noticeable conformational changes in the protein upon ligand-binding. A significant change in the kink of the S6-transmembrane helix was observed. Inter-chain distances between the crucial residues Y652 and F656 (present below the ion-selectivity filter), their side-chain orientation and hydrogen bonding indicated a probable collapse of the pore. These changes may infer the initiation in transition of hERG from an open to an inactive state. Hence, these findings would help in designing compounds devoid of hERG inhibition with reduced cardiotoxicity. Communicated by Ramaswamy H. Sarma

The Potential Benefit of Expedited Development and Approval Programs in Precision Medicine.

Background: Increased understanding of the molecular causes of disease has begun to fulfill the promise of precision medicine with the development of targeted drugs, particularly for serious diseases with unmet needs. The drug approval regulatory process is a critical component to the continued growth of precision medicine drugs and devices. To facilitate the development and approval process of drugs for serious unmet needs, four expedited approval programs have been developed in the US: priority review, accelerated approval, fast track, and breakthrough therapy programs. Methods: To determine if expedited approval programs are fulfilling the intended goals, we reviewed drug approvals by the US Food and Drug Administration (FDA) between 2011 and 2017 for new molecular entities (NMEs). Results: From 2011 through 2017, the FDA approved 250 NMEs, ranging from 27 approvals in 2013 to 46 in 2017. The NME approvals spanned 22 different disease classes; almost one-third of all NMEs were for oncology treatments. Conclusions: As these pathways are utilized more, additional legislative changes may be needed to re-align incentives to promote continued development of innovative drugs for serious unmet needs in a safe, efficacious, and affordable manner.

Particle Size Reduction Techniques of Pharmaceutical Compounds for the Enhancement of Their Dissolution Rate and Bioavailability

In pharmaceutical research and development, various new chemical entities (NCE) are found to be poorly water-soluble. Therefore, solubility enhancement, a key factor for higher bioavailability, is a major challenge in pharmaceutical industries. Particle size reduction is one such method that increases the surface area of the pharmaceutical compounds and subsequently leads to a higher dissolution rate and bioavailability. Conventional processes such as milling, high-pressure homogenization, and spray drying are well established and widely used for particle size reduction. However, a few disadvantages such as a broader particle size distribution (PSD) and thermal and chemical degradation of the product are major concerns for the product quality. Non-conventional processes such as liquid anti-solvent crystallization, supercritical anti-solvent process, rapid expansion of supercritical solutions, particles from gas saturated solutions, and pulsed laser ablation are emerging as potential alternatives to overcome the disadvantages of conventional processes. This review critically summarizes the milling, spray drying, high-pressure homogenization, liquid anti-solvent crystallization, spray freeze-drying, supercritical carbon dioxide $$(\mathrm{SC C}{\mathrm{O}}_{2})$$ –based micronization processes, pulsed laser ablation and combinative techniques. The success of these processes in enhancing the dissolution rate and bioavailability of many active pharmaceutical ingredients (APIs) has been critically examined. The advantages and limitations of these processes are also discussed. Finally, opportunities for future research are also proposed.