Pharmaceutical Drug Products Research Articles

PROSPECTS AND CHALLENGES OF PHARMACEUTICAL BIOTECHNOLOGY

Biotechnology is a broad area of biology, involving the use of living systems and organisms to develop products. Depending on the tools and applications, it often overlaps with related scientific fields. In the late 20th and early 21st centuries, biotechnology has expanded to include new and diverse sciences, such as genomics, recombinant gene techniques, applied immunology, and development of pharmaceutical therapies and diagnostic tests. Biotechnology has also led to the development of antibiotics. Biotechnology has applications in four major industrial areas, including health care (medical), crop production and agriculture, non-food (industrial) uses of crops and other products and environmental uses. In medicine, modern biotechnology has many applications in areas such as pharmaceutical drug discoveries and production, pharmacogenomics, and genetic testing. Pharmaceutical biotechnology is a relatively new and growing field in which the principles of biotechnology are applied to the development of drugs. A majority of therapeutic drugs in the current market are bio formulations, such as antibodies, nucleic acid products and vaccines. Such bio formulations are developed through several stages that include: understanding the principles underlying health and disease the fundamental molecular mechanisms governing the function of related biomolecules synthesis and purification of the molecules determining the product shelf life, stability, toxicity and immunogenicity drug delivery systems patenting and clinical trials. This review article describes the purpose of biotechnology in pharmaceutical industry, particularly pharmaceutical biotechnology along with its prospects and challenges.

Twists and Turns in the Salicylate Catabolism of Aspergillus terreus, Revealing New Roles of the 3-Hydroxyanthranilate Pathway.

In fungi, salicylate catabolism was believed to proceed only through the catechol branch of the 3-oxoadipate pathway, as shown, e.g., in Aspergillus nidulans However, the observation of a transient accumulation of gentisate upon the cultivation of Aspergillus terreus in salicylate medium questions this concept. To address this, we have run a comparative analysis of the transcriptome of these two species after growth in salicylate using acetate as a control condition. The results revealed the high complexity of the salicylate metabolism in A. terreus with the concomitant positive regulation of several pathways for the catabolism of aromatic compounds. This included the unexpected joint action of two pathways-3-hydroxyanthranilate and nicotinate-possibly crucial for the catabolism of aromatics in this fungus. Importantly, the 3-hydroxyanthranilate catabolic pathway in fungi is described here for the first time, whereas new genes participating in the nicotinate metabolism are also proposed. The transcriptome analysis showed also for the two species an intimate relationship between salicylate catabolism and secondary metabolism. This study emphasizes that the central pathways for the catabolism of aromatic hydrocarbons in fungi hold many mysteries yet to be discovered.IMPORTANCE Aspergilli are versatile cell factories used in industry for the production of organic acids, enzymes, and pharmaceutical drugs. To date, bio-based production of organic acids relies on food substrates. These processes are currently being challenged to switch to renewable nonfood raw materials-a reality that should inspire the use of lignin-derived aromatic monomers. In this context, aspergilli emerge at the forefront of future bio-based approaches due to their industrial relevance and recognized prolific catabolism of aromatic compounds. Notwithstanding considerable advances in the field, there are still important knowledge gaps in the central catabolism of aromatic hydrocarbons in fungi. Here, we disclose a novel central pathway, 3-hydroxyanthranilate, defying previously established ideas on the central metabolism of the aromatic amino acid tryptophan in Ascomycota We also observe that the catabolism of the aromatic salicylate greatly activated the secondary metabolism, furthering the significance of using lignin-derived aromatic hydrocarbons as a distinctive biomass source.

A linear scale-up approach to fluid bed granulation

Fluid bed granulation (FBG) is used extensively in the pharmaceutical industry and it is known to be a complex process, because the final product quality of the FBG process is determined by a complex interplay between the process parameters, fluid dynamics, and material properties. Due to this complexity, the FBG process is inherently nonlinear and as such difficult to scale-up.The field of chemical engineering has shown that complex nonlinear processes can be assumed to be linear under limiting conditions. We leverage this idea and present a linear scale-up approach (LiSA) to the FBG process. We derive the key LiSA equation from first principles, and then use it in combination with the similarity principle for scale-up purposes.Furthermore, we present a novel regression-based LiSA. The regression-based LiSA is founded on the hypothesis that there is a linear relationship between the moisture content and a scaling parameter called the Maus factor. This hypothesis is based on our experience and it is shown to be plausible due to high R2 values ranging from 0.86 to 0.98. Moreover, we successfully demonstrate that LiSA is effective under typical industrial process settings by applying it to two different formulations during pharmaceutical drug product development.

DRUG POLYMORPHISM IDENTIFICATION USING FOURIER TRANSFORM-RAMAN SPECTROSCOPY: A COMPARATIVE STUDY OF LAMIVUDINE AND FINASTERIDE DRUGS

Objectives: Maintaining the quality of the pharmaceutical drug product during its shelf life is highly desirable. The crystalline form of the drug having the great thermodynamic stability is essential for the manufacturers in pharmaceutical industry in view of their profit and also for the safety of the customer. Many pharmaceutical drugs have the tendency to exhibit polymorphism which is unwanted for pharmaceutical companies, where they have experienced market shortages due to these unpredicted polymorphic and/or pseudomorphic changes. The property of a drug exhibiting more than one crystal form is considerably regarded as polymorphism and each of the crystalline form has its own physicochemical properties, namely, solubility, heat capacity, melting point, and sublimation point. To relieve this ultimate effect on the drug quality and stability, a prior detection of polymorphism in the final dosage form is highly recommended. Hence, many analytical techniques have been proposed for the detection of polymorphism in pharmaceutical drug products.
 Methods: Fourier transform (FT)-Raman spectrometer is used for the investigation of drug polymorphism and the instrument is advanced with charge coupled device detectors, ease of sample preparation and handling, mitigation of sub-sampling problems using different geometric laser irradiance patterns and having different optical components of Raman spectrometers.
 Results: In this work, we carefully studied the Raman spectral patterns for Lamivudine as well as Finasteride drug substances for the detection of polymorphism. Further, we have highlighted the advantages of FT-Raman spectroscopy over other polymorphism detection techniques. For example, Raman spectra showed invariably sharp, well resolved bands compare to IR spectra due to the minor contribution of overtone vibrations in Raman spectra, resulting in much less broadening and a better resolution of bands. Besides, Raman spectroscopy does not suffer from the sampling problems that are common in X-ray powder diffraction, where preferred orientation and specimen displacements are serious restrictions for the application of quantitative method.
 Conclusion: Here, in this paper, we are presented and compared the experimental results regarding the detection of polymorphism in Lamivudine and Finasteride drugs using FT-Raman spectroscopy, to illustrate the advantages of the technique in the detection of polymorphism over other techniques.

Comparative evaluation on effect of drying methods on physicochemical characterization of wild bitter gourds Momordica charantia var. Muricata

Momordica charantia var. muricata has shown a higher rate of antibacterial properties due to presence of specific secondary metabolites. In this paper, we have used an indigenously built convectional drying system that unlike other available systems does not depend on hot air rather a different approach altogether. The physicochemical characterization is compared amongst vacuum-assisted convectional drying, freeze drying and microwave drying, using instrumental analysis and wet-chemistry. The pharmacological efficacy of wild bitter gourd (WBG) in treatment of various ailments and medical conditions inclusive of diabetes mellitus, is a research gap with limited in-vivo studies available. WBG has shown effectiveness against inoculums of gram positive and gram-negative bacteria even post this drying technique. The dried WBG showed appreciable antioxidant activity (DPPH) making it a viable option to be utilized as an ingredient in production of fried products to extend the rancidity period. The evaluation of physical properties including color, water activity, shrinkage ratio and rehydration ratio have been discussed. Retention of total phenolic content (TPC), chlorophyll and ascorbic acid, post drying was evaluated. The research aims to explore chemical potency and changes in physicochemical parameters of WBG upon different drying techniques. Practical Application: Since the medicinal value is higher; making it available for commercial production of nutraceuticals and pharmaceutical drugs, the product requires to be dried and powdered, and the nutritive composition needs to be evaluated. Utilization as ingredient in production of fried products to extend the rancidity period. The retention of certain nutritive compounds in wild bitter gourd powder (WBGP) can be utilized as value added product and as ingredient in development of functional foods and beverages based on its medicinal properties.

Development, Validation of RP-HPLC Method and GC MS Analysis of Desloratadine HCL and IT"s Degradation Products

Introduction: Efficacy and safety of drug therapy is directly related to the stability of active pharmaceutical ingredient (API) and drug product used. Forced degradation studies (also called stress testing) are performed for better understanding of API and drug product stability. Thus, stress testing is a prognostic research tool used to ascertain stability of drug molecules and provide support for developing a stability-indicating method. Aim: The research aim is Development, Validation of RP-HPLC Method and GC MS Analysis of Desloratadine HCL and Its Degradation Products. Objective: The objective of the current study was to develop a validated specific stability-indicating reversed-phase liquid chromatographic method for the quantitative determination of Desloratadine HCl in bulk samples in the presence of degradation products. Method: Desloratadine HCL was subjected to variable pH, oxidative, dry heat and photolytic stress condition as per ICH guideline for the stability study. Stressed samples were further studied by the validated RP-HPLC method and also studied by GC-MS to characterize degradation products (Fig 15). Result: At oxidative stress, degradation products were generated and detected by GCMS. Slight degradation was observed in acidic and alkaline stress while no degradation was observed in other stress conditions. Separation of degradation products from pure drug was achieved on C18 column 5µ (4.6 X 250 mm) using the mobile phase consists a mixture of Orthophosphoric acid (0.1%V/V), Acetonitrile and Methanol (50:35:15 V/V/V). The detection was carried out at 242 nm. The proposed validated LC method was used to quantify the stressed test solutions in order to ascertain stability-indicating potential of the method. Conclusion: The established LC approach has been shown to be suitable for determining the quality of Desloratadine HCl from its dosage form and assessing its stability when required.

A solvent-free headspace GC/MS method for sensitive screening of N-nitrosodimethylamine in drug products.

A solvent-free headspace gas chromatography-mass spectrometry (SF-HS-GC/MS) method was developed and validated for screening N-nitrosodimethylamine (NDMA) in various active pharmaceutical ingredients (APIs) and drug products. Experimental parameters such as incubation temperature, incubation time, and sample volume in solvent-free headspace conditions were optimized. The developed SF-HS-GC/MS method was validated in terms of linearity, limit of quantification (LOQ), precision, and accuracy. The results indicated excellent linearity from 5 to 500 ng g-1 with correlation coefficients higher than 0.9999. The LOQ of this method was 5 ng g-1 and matrix effects ranged from 0.97 to 1.11. The accuracy ranged from 92.77 to 106.54% and the precision RSDs were below 5.94%. No significant matrix effect was observed for any of the drug products. Also, artefactual NDMA formation in ranitidine, nizatidine, and metformin was investigated under HS conditions. Adjusted (mild) SF-HS conditions were suggested for precise quantification of NDMA in positive drug products by GC/MS. The present SF-HS-GC/MS method is a promising tool for the screening and determination of toxic NDMA in APIs and drug products.

Manganese-Catalyzed Chlorosulfonylation of Terminal Alkene/Yne <i>Via</i> Convergent Paired Electrolysis

Convergent paired electrolysis is an energy-efficient model in organic synthesis. Whereas the main obstacle is the matching properties of intermediates generated in two electrodes. Herein, we develop a manganese-catalyzed atom-transfer radical addition of terminal aryl alkenes and alkynes with sulfonyl chlorides, where manganese salt plays the role of chlorine atom-transfer catalyst as well as redox mediator. This method generates analogues of chlorosulfonylated products in high regio- and stereoselectivity, which are derivatives of pharmaceutical drug and natural products.

A Comprehensive Review of Regulatory Requirements and Registration Process of Pharmaceutical Drug Products in CIS Countries

Background: The CIS region has a potential market for India. The registration of the drug products in CIS regions is a challenging task because these countries have no harmonized regulatory organization. The CIS region includes 12 countries such as Russia, Kyrgyzstan, Ukraine, Uzbekistan, Kazakhstan, Tajikistan, Turkmenistan, Armenia, Azerbaijan, Belarus, Georgia and Moldova, which require different regulatory guidelines for medicinal product registration as per their FDA guidelines. The different guidelines for the same region become a challenging task for the manufacturer and exporter. The registration of the same product for different countries of CIS is not possible with the same dossier due to the lack of their regulatory harmonization. These countries obey their country-specific dossier format, so to target these market manufacturers and exporters needs to submit different dossier documents for different countries. But Ukraine and Kazakhstan have harmonization and it varies in Uzbekistan and Tajikistan. Ukraine and Kazakhstan are also imposing strict rules and expecting USFDA level documents for approval. Conclusion: The overall conclusion is that harmonization in CIS is highly imbalanced, which affects both time and cost for product registration. Harmonization is the need of the era for easy product registration, and it will be beneficial for the manufacturer, regulator, importer, exporter, and to access medicines of high public health value.

Drug Registration requirements for Pharmaceuticals in Emerging markets

Registration of pharmaceutical drug products in emerging market is maximum worrying task. Although the requirements are harmonized in regulated international locations by way of CTD (Common technical document) submitting, yet others have considerable diversity in necessities. International conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has brought regulatory authorities and pharmaceutical industries of US, Japan and Europe collectively for various factors of drug registration. But there is no such harmonized guideline for rising marketplace besides Association of Southeast Asian Nations (ASEAN) and Gulf Co-operation Council (GCC) where harmonization exists in clusters with their mutual situation. Quality, Safety and Efficacy information has significance importance in dossier registration. Pharmaceutical Industries has to conform with regulatory requirement in Emerging market and for betterment of public Health and protection. The business importance of markets is increasing globally. It is important for pharmaceutical enterprise to address the regulatory necessities for betterment of public and to ensure their place in the marketplace. The review additionally explains a short approximately extraordinary regulatory requirement for Registration of drug product in Emerging market and comparative data for registration of dossier software in Emerging marketplace.

Challenges for Cell-Based Medicinal Products From aPharmaceutical Product Perspective.

Advanced therapy medicinal products (ATMPs), such as somatic cell-therapy medicinal products or tissue-engineered products for human use, offer new and potentially curative opportunities to treat yet untreatable diseases or disorders. For cell-therapy medicinal products (CBMPs), multiple stability and quality challenges exist and relate to the cellular composition and unstable nature of these parenteral preparations. It is the aim of this review to discuss open questions and problems associated with the development, manufacturing and testing of CBMPs from a pharmaceutical drug product perspective. This includes safety, storage and handling, particulates, the choice of container closure systems and integrity. Analytical methods commonly used to evaluate the quality of the final CBMP to ensure patient's safety will be discussed. Particulate contamination in final products deserve special attention since CBMPs cannot be sterile filtered. Visible and sub-visible particles may represent environmental contaminations or may form during storage. They may be introduced from processing materials such as single use product contact materials, ancillary materials, or any components such as primary packaging used for the final product. Currently available analytical methods for detecting particulates may not be easily applicable to CBMPs due to their inherent particulate nature and appearance.

One‐Pot Access towards 4,5‐Disubstituted 2‐Amino‐1H‐imidazoles Starting from Mannich Substrates and their Transformation Utilities

An efficient protocol for the preparation of 4,5‐functionalised 2‐amino‐1H‐imidazoles as fragment‐like structures was developed in isolated yields up to 95 %. The demonstrated one‐pot manner includes an intramolecular oxidative annulation and ring cleavage sequence starting from Mannich precursors. The suggested one‐pot sequential synthetic methodology is easy to apply in automatic and robotic chemistry laboratories for which a rapidly increasing demand is foreseen because of the ongoing revolution in the field of continuous manufacturing of pharmaceutical drug substances and products. Further transformation utilities such as Groebke–Blackburn–Bienaymé 3CR and the formation of marine alkaloid analogs were also represented.

Application of Measurement Uncertainty on Conformity Assessment in Pharmaceutical Drug Products.

Conformity assessment in pharmaceutical drug products usually are based on analytical results. An analytical result always is associated with an uncertainty which must be considered in a compliance assessment. The objective of the present project aims to estimate the measurement uncertainty associated with the results of average weight, assay, uniformity of content, and dissolution testing in ranitidine tablets manufactured by two different companies (X and Y). The uncertainty was evaluated using the Monte Carlo method. The particular and total risks of false acceptance decisions (consumers' risks) were also estimated by the Monte Carlo method. The results for ranitidine tablets manufactured by company X were (359.2 ± 2.7) mg of average weight, (108.6 ± 1.6)% of assay, (11.4 ± 2.8) of acceptance value for uniformity of content, and (89.4 ± 1.3)% for dissolution testing. The results for company Y were (312.5 ± 0.9) mg, (107.0 ± 1.4)%, (7.2 ± 1.7), and (93.6 ± 1.3)%, respectively. A 95% confidence level was adopted. According to results obtained from the Monte Carlo simulations, the results of average weight, assay of ranitidine, and uniformity of content are significantly correlated due to shared analytical steps. The correlation between values significantly affected the risk of false decisions. Consumers' risks were estimated for both ranitidine tablets and their results ensure compliance for ranitidine tablets manufactured by companies X and Y. The use of measurement uncertainty is an important issue regarding the conformity/non-conformity assessment of pharmaceutical products.

Insect and avian threats to the industrial production of balanites fruit in Eritrea

Balanites fruit pulp and seed kernel contain considerable amount of steroidal saponins, which are used as raw material for the production of pharmaceutical drugs. However, insect and avian pests are the key limiting factors in balanites production. This study was conducted to record the causal insect and avian pests and level of their infestation. Balanites fruits fallen on the ground were collected at regular intervals for two fruiting seasons at Keren, Eritrea. The fruits were put in polybags and stored at room temperature. The emerging insects were counted and percent infestation was calculated. The insects identified were balanites stone borer, Eublemma (= Eupsoropsis) robertsi (Lepidoptera: Erebidae) and carob moth, Apomyelois (=Ectomyelois) ceratoniae (Lepidoptera: Pyralidae). Eublemma robertsi larva consumed the kernel and bored into the stone with one exit hole (ca. 3 mm) at pre-pupal stage whereas A. ceratoniae larvae infested and contaminated fruit pulp with faecal waste. More than 70% of fruits collected during October and November were infested by E. robertsi and oviposition of 1–3 eggs were found on 73% of examined fruits. Damage from A. ceratoniae was unnoticeable in field-collected fruits but larval infestation was observable after one month of storage. The speckled mousebird, Colius striatus (Coliiformes: Coliidae), was the most frequent avian visitor, which not only nibbled on fruits attached to branches but also caused drop of fruits to the ground. Fruit damage caused by birds ranged 58 to 95% during the two fruiting seasons.

Antibiotic activity and resistance of lactic acid bacteria and other antagonistic bacteriocin-producing microorganisms

Introduction. Increased resistance of microorganisms to traditional antibiotics has created a practical need for isolating and synthesizing new antibiotics. We aimed to study the antibiotic activity and resistance of bacteriocins produced by lactic acid bacteria and other microorganisms.
 Study objects and methods. We studied the isolates of the following microorganism strains: Bacillus subtilis, Penicillium glabrum, Penicillium lagena, Pseudomonas koreenis, Penicillium ochrochloron, Leuconostoc lactis, Lactobacillus plantarum, Leuconostoc mesenteroides, Pediococcus acidilactici, Leuconostoc mesenteroides, Pediococcus pentosaceus, Lactobacillus casei, Lactobacillus fermentum, Bacteroides hypermegas, Bacteroides ruminicola, Pediococcus damnosus, Bacteroides paurosaccharolyticus, Halobacillus profundi, Geobacillus stearothermophilus, and Bacillus caldotenax. Pathogenic test strains included Escherichia coli, Salmonella enterica, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus mycoides, Alcaligenes faecalis, and Proteus vulgaris. The titer of microorganisms was determined by optical density measurements at 595 nm. 
 Results and discussion. We found that eleven microorganisms out of twenty showed high antimicrobial activity against all test strains of pathogenic and opportunistic microorganisms. All the Bacteroides strains exhibited little antimicrobial activity against Gramnegative test strains, while Halobacillus profundi had an inhibitory effect on Gram-positive species only. The Penicillium strains also displayed a slight antimicrobial effect on pathogenic test strains.
 Conclusion. The antibiotic resistance of the studied lactic acid bacteria and other bacteriocin-producing microorganisms allows for their use in the production of pharmaceutical antibiotic drugs.

Predicting the environmental emissions arising from conventional and nanotechnology-related pharmaceutical drug products

Today, environmental pollution with pharmaceutical drugs and their metabolites poses a major threat to the aquatic ecosystems. Active substances such as fenofibrate, are processed to pharmaceutical drug formulations before they are degraded by the human body and released into the wastewater. Compared to the conventional product Lipidil® 200, the pharmaceutical product Lipidil 145 One® and Ecocaps take advantage of nanotechnology to improve uptake and bioavailability of the drug in humans. In the present approach, a combination of in vitro drug release studies and physiologically-based biopharmaceutics modeling was applied to calculate the emission of three formulations of fenofibrate (Lipidil® 200, Lipidil 145 One®, Ecocaps) into the environment. Special attention was paid to the metabolized and non-metabolized fractions and their individual toxicity, as well as to the emission of nanomaterials. The fish embryo toxicity test revealed a lower aquatic toxicity for the metabolite fenofibric acid and therefore an improved toxicity profile. When using the microparticle formulation Lipidil® 200, an amount of 126 mg of non-metabolized fenofibrate was emitted to the environment. Less than 0.05% of the particles were in the lower nanosize range. For the nanotechnology-related product Lipidil 145 One®, the total drug emission was reduced by 27.5% with a nanomaterial fraction of approximately 0.5%. In comparison, the formulation prototype Ecocaps reduced the emission of fenofibrate by 42.5% without any nanomaterials entering the environment. In a streamlined life cycle assessment, the lowered dose in combination with a lowered drug-to-metabolite ratio observed for Ecocaps led to a reduction of the full life cycle impacts of fenofibrate with a reduction of 18% reduction in the global warming potential, 61% in ecotoxicity, and 15% in human toxicity. The integrated environmental assessment framework highlights the outstanding potential of advanced modeling technologies to determine environmental impacts of pharmaceuticals during early drug development using preclinical in vitro data.

Developing patient-centric medicines for older people: Reflections from the draft EMA paper on the pharmaceutical development of medicines for use in the older population.

Increased global longevity requires a re-evaluation of current structures in society to adapt to the consequential demographic shift. As (very) old people are prone to impaired human organ and body functions resulting in, for example, multimorbidity, polypharmacy, hospitalisation and problems in medication management, it is increasingly acknowledged that re-evaluations should include the suitability of pharmaceutical patient care as one of the cornerstones of public health. Following the 2011 European Medicines Agency (EMA) Geriatric Strategy, in 2017 the EMA published the draft "Reflection paper on the pharmaceutical development of medicines for use in the older population". The draft paper was opened for public consultation and specific attention and feedback (either supportive or with a proposal for revision) was asked on three design aspects: tablet breaking, drug administration through enteral feeding tubes and medication management. Following publication, the draft paper was presented at two public conferences attended by participants from different disciplines. This manuscript is intended to draw the attention of different stakeholder parties to the urgent need to collaborate on the emerging issues arising from increasing longevity and multimorbidity, and especially those associated with pharmaceutical patient care and drug product design, including the need for collaborative research into existing or emerging knowledge gaps. The manuscript focuses on the three aforementioned aspects of pharmaceutical development (tablet breaking, drug administration through enteral feeding tubes and medication management) as these highly relate to medication safety and efficacy and constitute persistent and typical challenges for older people, caregivers and healthcare professionals in daily clinical practice.

X-ray Powder Diffraction Spectroscopy as a Robust Tool in Early Predicting Bioavailability of Pharmaceutical Formulation Containing Polymorphic Drug Substance

: X-ray powder diffraction (XRPD) is a unique, solid-state analytical tool used to study the 3D structure of small or macromolecules by their x-ray diffraction or scattering patterns. X-ray diffraction by a crystal reflects the periodicity of crystal architecture; any imperfections within the crystal architecture can be easily identified by its poor diffraction pattern. Recently, an open crystallography database reported that more than 85 % of drug compounds are crystalline and exist in different polymorphic states. Physicochemical properties of pharmaceutical drug products composed of active pharmaceutical ingredients (APIs) and excipients are interdependent on the physical state and forms in which APIs are distributed in excipients that determine the in-vivo and ex-vivo performance of the product. Amorphous APIs have relatively higher dissolution and bioavailability than crystalline form but with lower phase stability. During the formulation development and storage phase, the conversion is higher that largely impacts the bioavailability of the drug product. In this manuscript, we have presented the case study of itraconazole and apigenin; both are crystalline APIs, that, with the help of solid dispersion technology, are converted into amorphous drug products with enhanced oral bioavailability. The realtime monitoring of the physical form of API in the formulation was possible with the help of XRPD and other supporting data obtained from differential scanning calorimeter (DSC), which can be correlated with the dissolution and in-vivo performance of the formulation.

Chemical reactor/compounding vessel fingerprinting: Scale-up/down considerations for homogeneous and heterogeneous mixing using computational fluid dynamics

The compounding process is a part of the preparation of a pharmaceutical drug product and is governed by the hydrodynamic characteristics inside the industrial mixing vessel. For the development of a small-scale model of the vessel that would mimic mixing on the industrial-level, these characteristics should be replicated. An appropriate design can be obtained by considering computational fluid dynamics (CFD) calculations, which acknowledge the geometric specifics and fluid behavior in the system. For the appropriate scale-down model design, the mixing process of the fluid inside the industrial compounding vessel was evaluated as well as the movement of the particles that undergo dissolution. The calculated fluid velocities along the streamlines and particle relative velocities along their trajectories provided a description that is specific for a given system. This particular vessel fingerprint can be used for evaluating the suitability of the developed design. Tracer tests were also performed in order to assess the rate of the homogenization process in the large and small scale vessels for the case of a local change of concentration, which occurs upon the addition of substances/excipients. By taking into account the calculated particle slip velocities, the dissolution of particles was modeled by acknowledging the dissolution kinetics and mass transfer. Finally, the designed scale-down mixing vessel was fabricated and tested.

Risk Assessment, Screening and Control of Elemental Impurities in Pharmaceutical Drug Products: A Review

This article describes and reviews the steps involved in risk assessment of the twenty-four (24) potential elemental impurities in pharmaceutical drug products, as per the permitted daily exposure limits. Screening and estimation of prescribed elemental impurities in pharmaceutical drug substances, inactive excipients and drug products by inductively coupled plasma mass spectrometry or inductively coupled plasma optical emission spectrometry and their controls involved are also reviewed, as referred in the general chapters <232> & <233> of the United States Pharmacopoeia, Q3D guideline for elemental impurities as per international conference on harmonization and q3d elemental impurities: guidance for industry as per U. S., Food and Drug Administration USFDA.