Polymorphism control of active pharmaceutical ingredients

Рolymorphism is receiving increasing attention due to its influence on the physicochemical and pharmacological properties of the active pharmaceutical ingredients (API) while maintaining the molecular structure. This review is devoted to the problem of APIs phase state control both at the development stage and during the circulation of the drug. The term «polymorphism» has different definitions depending on the branch of science. There is no unambiguous solution to this issue in the regulatory documentation of pharmaceutical industry either. Based on the analysis of literary sources, the article presents a comparison of pharmacopeia methods, recommended in Russian and foreign regulatory documents for the analysis of polymorphism of medicinal substances, including state pharmacopeias of Russia, Belarus, Kazakhstan, the USA, and Japan, as well as international pharmacopeias of the European Economic Union and the Eurasian Economic Union. The trend on using a complex of high-tech equipment is revealed. A systematic approach to analysis based on X-ray diffraction, thermal, spectral, microscopic, biological, and physical methods for determining constants makes it possible not only to identify the polymorphic modification of API, but also to characterize its structure, morphology, physicochemical properties and pharmacological activity. In the Russian Federation, the phenomenon of polymorphism is being studied especially intensively, and some control methods, such as biological methods, are validated only in Russian pharmacopeia. A promising direction for further research is the improvement and harmonization of regulatory documentation within the framework of this chemical and technological field of pharmacy. A global approach will help to reduce not only the probability of poor-quality products entering the market, but also the costs of establishing the authenticity of the active pharmaceutical ingredient produced.

Download Full-text

Quality Assessment of Antibiotic Oral Drug Formulations Marketed In Katsina State, Nigeria

Asian Journal of Pharmaceutical Research and Development ◽

10.22270/ajprd.v7i6.615 ◽

1970 ◽

Vol 7 (6) ◽

pp. 6-10

Author(s):

Mukhtar Gambo Lawal ◽

Muhammad Dauda Mukhtar ◽

Abdulkadir Magaji Magashi

Keyword(s):

Active Ingredient ◽

Active Pharmaceutical Ingredient ◽

Oral Drug ◽

Active Pharmaceutical Ingredients ◽

Hplc Assay ◽

Drug Formulations ◽

Percentage Content ◽

Pharmaceutical Ingredients ◽

Three Samples ◽

High Incidence

There are increasing reports on the high incidence of substandard drugs, especially in developing countries.Pharmaceutical products have been reported to contain either no, low, or excessive amounts of the active pharmaceutical ingredient (API). Inview of the above, 112 samples of six different antibiotic oral drug formulations were evaluated for chemical quality by assessing the presence and the percentage content of the stated active pharmaceutical ingredients using validated HPLC assay as described in the official monograph of the British and United Stated pharmacopoeia. The result indicates that 43 (38.4%) had active ingredients outside the set pharmacopoeial limit and therefore were non-compliant to the BP and the USP specifications for percentage content. Ampiclox and Cotrimoxazole had the highest proportion of samples with active ingredient outside the pharmacopoeial limit, and in three samples (one Augmentin and two Ampiclox), no active ingredient was detected. The presence of API lower than the claimed content declared on the packaging was the primary cause of non-compliance. The potential implications of the use of substandard drugs are treatment failure and the development of drug-resistance.

Download Full-text

(1R,3S)-3-(1H-Benzo[d]imidazol-2-yl)-1,2,2-trimethylcyclopentane-1-carboxylic acid as a new anti-diabetic active pharmaceutical ingredient

Acta Crystallographica Section E Crystallographic Communications ◽

10.1107/s2056989020010439 ◽

2020 ◽

Vol 76 (9) ◽

pp. 1407-1411

Author(s):

Sergiy M. Kovalenko ◽

Irina S. Konovalova ◽

Sergiy I. Merzlikin ◽

Vladimir P. Chuev ◽

Dmitry V. Kravchenko

Keyword(s):

Active Pharmaceutical Ingredient ◽

Ethanol Solution ◽

Membered Ring ◽

Active Pharmaceutical Ingredients ◽

Pharmaceutical Ingredients ◽

Compound C ◽

Intermolecular Contacts ◽

The Mean ◽

Camphoric Acid

The chiral title compound, C16H20N2O2, which can be used for producing active pharmaceutical ingredients for treatment of type 2 pancreatic diabetes and other pathologies dependent on insulin resistance, was prepared from (1R,3S)-camphoric acid and o-phenylenediamine. It crystallized from an ethanol solution in the chiral monoclinic P21 space group. The five-membered ring adopts a twisted conformation with the methyl-substituted C atoms displaced by −0.273 (5) and 0.407 (5) Å from the mean plane through the other three atoms. In the crystal, molecules are linked by O—H...N hydrogen bonds, forming chains along the a-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the intermolecular contacts present in the crystal.

Download Full-text

Stability of Pharmaceutical Co-Crystals at Humid Conditions Can Be Predicted

Pharmaceutics ◽

10.3390/pharmaceutics13030433 ◽

2021 ◽

Vol 13 (3) ◽

pp. 433

Author(s):

Heiner Veith ◽

Maximilian Zaeh ◽

Christian Luebbert ◽

Naír Rodríguez-Hornedo ◽

Gabriele Sadowski

Keyword(s):

Pharmaceutical Formulations ◽

Active Pharmaceutical Ingredient ◽

Storage Conditions ◽

Pharmaceutical Products ◽

Active Pharmaceutical Ingredients ◽

Statistical Associating Fluid Theory ◽

Pharmaceutical Ingredients ◽

Soluble Solid ◽

Fluid Theory ◽

The Stability

Knowledge of the stability of pharmaceutical formulations against relative humidity (RH) is essential if they are to become pharmaceutical products. The increasing interest in formulating active pharmaceutical ingredients as stable co-crystals (CCs) triggers the need for fast and reliable in-silico predictions of CC stability as a function of RH. CC storage at elevated RH can lead to deliquescence, which leads to CC dissolution and possible transformation to less soluble solid-state forms. In this work, the deliquescence RHs of the CCs succinic acid/nicotinamide, carbamazepine/nicotinamide, theophylline/citric acid, and urea/glutaric acid were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These deliquescence RH values together with predicted phase diagrams of CCs in water were used to determine critical storage conditions, that could lead to CC instability, that is, CC dissolution and precipitation of its components. The importance of CC phase purity on RH conditions for CC stability is demonstrated, where trace levels of a separate phase of active pharmaceutical ingredient or of coformer can significantly decrease the deliquescence RH. The use of additional excipients such as fructose or xylitol was predicted to decrease the deliquescence RH even further. All predictions were successfully validated by stability measurements at 58%, 76%, 86%, 93%, and 98% RH and 25 °C.

Download Full-text

Systèmes à libération contrôlée pH-dépendants de principes actifs hydrophobes à partir d’oléogels

International Journal of Biological and Chemical Sciences ◽

10.4314/ijbcs.v15i2.2 ◽

2021 ◽

Vol 15 (2) ◽

pp. 388-398

Author(s):

Papa Mady Sy ◽

Peggy Ngadou Ntchobaha ◽

Sidy Mouhamed Dieng ◽

Louis Augustin D. Diouf ◽

Alphonse R. Djiboune ◽

...

Keyword(s):

Controlled Release ◽

Large Scale ◽

Sol Gel ◽

Active Pharmaceutical Ingredient ◽

Sub Saharan Africa ◽

Gelling Agent ◽

Active Pharmaceutical Ingredients ◽

Medium Ph ◽

Pharmaceutical Ingredients ◽

Ph Dependent

Les rhumatismes inflammatoires chroniques sont une cause importante d'invalidité dans le monde entier. De ce fait, les affections rhumatismales chroniques font peser une lourde charge sociale et économique sur toutes les sociétés, pas seulement sur celles où l’espérance de vie est élevée. L’objectif principal de ce travail était d’étudier le profil de libération pH-dépendante de principes actifs hydrophobes à partir d’oléogels oraux et/ou cutanés. La formulation des oléogels a été réalisée selon une méthode sol-gel, reproductible à grande échelle. La caractérisation et le suivi dans le temps ont montré une bonne stabilité des oléogels. Les valeurs de pH des oléogels étaient globalement acides (entre 4,3 et 5,8) et dépendaient de la quantité de gélifiant utilisée. Les études de libération du kétoprofène, principe actif hydrophobe, en fonction du pH des milieux de dissolution ont montré des profils de libération d’une cinétique du premier ordre d’équation 𝑷𝒕=𝑷𝟎+𝑨.𝒆𝒙𝒑𝑲𝒕 avec des coefficients de détermination proches de 1 (milieux à pH égal à 1,2 et 5,5). Une meilleure libération du kétoprofène a été obtenue dans un milieu intestinal simulé (pH égal à 6,8) pour les formulations qui présentaient déjà une saturation en milieu gastrique simulé (pH égal à 1,2). Cette étude qui a permis de formuler, d’évaluer et de modéliser le profil de libération du kétoprofène à partir d’oléogels peut constituer une étape importante dans un objectif de souveraineté thérapeutique des pays d’Afrique subsaharienne notamment le Sénégal.Mots clés : Oléogels, rhumatismes inflammatoires chroniques, kétoprofène, libération contrôlée, pH-dépendant. English Title: pH-dependent controlled release systems of hydrophobic active pharmaceutical ingredients from oleogels Chronic inflammatory rheumatism is a major cause of disability around the world. As a result, chronic rheumatic diseases place a heavy social and economic burden on all societies, not just those with high life expectancy. The main objective of this work was to control the pH-dependent release of hydrophobic active pharmaceutical ingredients from oral and / or skin oleogels. The formulation of the oleogels was carried out using a sol-gel large-scale reproducible method. Characterization and monitoring over time have shown good stability of the oleogels. The pH values of the oleogels were overall acid (between 4.3 and 5.8) and depended on the amount of gelling agent used. The release studies of ketoprofen, a hydrophobic active pharmaceutical ingredient, as a function of the pH of the dissolution media have shown release profiles of first-order kinetics of equation 𝑷𝒕=𝑷𝟎+𝑨.𝒆𝒙𝒑𝑲𝒕 with coefficients of determination close to 1 (media at pH equal to 1.2 and 5.5). Better release of ketoprofen was obtained in simulated intestinal medium (pH equal to 6.8) for formulations which already exhibited saturation in simulated gastric medium (pH equal to 1.2). This study, which made it possible to formulate, evaluate and model the release profile of ketoprofen from oleogels, may constitute an important step in an objective of therapeutic sovereignty of the countries of sub-Saharan Africa, particularly Senegal.Keywords: oleogels - chronic inflammatory rheumatism - ketoprofen - controlled release – pH-dependent.

Download Full-text

Flow Synthesis Kinetics for Lomustine, an Anti-Cancer Active Pharmaceutical Ingredient

Reaction Chemistry & Engineering ◽

10.1039/d1re00184a ◽

2021 ◽

Author(s):

Samir Diab ◽

Mateen Raiyat ◽

Dimitrios I. Gerogiorgis

Keyword(s):

Heat Transfer ◽

Continuous Flow ◽

Active Pharmaceutical Ingredient ◽

Process Conditions ◽

Active Pharmaceutical Ingredients ◽

Batch Mode ◽

Flow Synthesis ◽

Pharmaceutical Ingredients ◽

Anti Cancer

Continuous flow synthesis of Active Pharmaceutical Ingredients (APIs) can offer access to process conditions that are otherwise hazardous when operated in batch mode, resulting in improved mixing and heat transfer,...

Download Full-text

Ultraflexible Liposome Nanocargo as a Dermal and Transdermal Drug Delivery System

Nanomaterials ◽

10.3390/nano11102557 ◽

2021 ◽

Vol 11 (10) ◽

pp. 2557

Author(s):

Kalvatala Sudhakar ◽

Shivkanya Fuloria ◽

Vetriselvan Subramaniyan ◽

Kathiresan V. Sathasivam ◽

Abul Kalam Azad ◽

...

Keyword(s):

Drug Delivery ◽

Transdermal Drug Delivery ◽

Active Pharmaceutical Ingredient ◽

Reticuloendothelial System ◽

Active Pharmaceutical Ingredients ◽

Transdermal Drug Delivery System ◽

Pharmaceutical Ingredients ◽

Therapeutic Drugs ◽

Vesicular Carriers ◽

Bioactive Agents

A selected active pharmaceutical ingredient must be incorporated into a cargo carrier in a particular manner so that it achieves its goal. An amalgamation of active pharmaceutical ingredients (APIs) should be conducted in such a manner that it is simple, professional, and more beneficial. Lipids/polymers that are known to be used in nanocarriers for APIs can be transformed into a vesicular formulation, which offers elegant solutions to many problems. Phospholipids with other ingredients, such as ethanol and water, form suitable vesicular carriers for many drugs, overcoming many problems related to poor bioavailability, poor solubility, etc. Ultraflexible liposomes are novel carriers and new frontiers of drug delivery for transdermal systems. Auxiliary advances in vesicular carrier research have been made, enabling polymer-coated ethanolic liposomes to avoid detection by the body’s immune system—specifically, the cells of the reticuloendothelial system. Ultraflexible liposomes act as a cargo system and a nanotherapeutic approach for the transport of therapeutic drugs and bioactive agents. Various applications of liposome derivatives in different diseases are emphasized in this review.

Download Full-text

Controlling phase transformation during milling in the pre-formulation of Active pharmaceutical Ingredients

Al Mustansiriyah Journal of Pharmaceutical Sciences ◽

10.32947/ajps.19.02.0402 ◽

2019 ◽

pp. 37-46

Keyword(s):

Drug Stability ◽

Active Pharmaceutical Ingredient ◽

Active Pharmaceutical Ingredients ◽

Inactive Compound ◽

Characterization Methods ◽

Factors Affecting ◽

Crystalline Materials ◽

Pharmaceutical Ingredients ◽

Pharmaceutical Processing ◽

As Solubility

A high percentage of active pharmaceutical ingredient are available in the insoluble crystalline phase. During pharmaceutical processing such as milling there are many issues can be initiated due to the transformation of this crystalline materials. Some trans-formation might be positively solving the active pharmaceutical ingredients (APIs) problems such as solubility and dissolution rate while others might negatively affect these factors which render the APIs into inactive compound. Therefore, during the pre-formulation study, all of these issues must be resolved to ensure drug stability and hence its bioavailability. This review will shed the light on the most popular transformations that happened, factors affecting them, and the characterization methods used for the detection of phase formed. The studying of these factors, will help to avoid them in future

Download Full-text

Indian Active Pharmaceutical Ingredient (API) Industry- An overview on Challenges, Opportunities & Regulatory prerequisites

International Journal of Drug Regulatory Affairs ◽

10.22270/ijdra.v9i2.471 ◽

2021 ◽

Vol 9 (2) ◽

pp. 66-76

Author(s):

Shefali Singh ◽

Harvinder Popli

Keyword(s):

Raw Materials ◽

Pharmaceutical Medicine ◽

Active Pharmaceutical Ingredient ◽

Point Of View ◽

Raw Material ◽

Manufacturing Cost ◽

Active Pharmaceutical Ingredients ◽

Pharmaceutical Ingredients ◽

Self Sufficiency ◽

History Of

Active pharmaceutical ingredient is a chemical compound which is most important raw material to formulate a finished pharmaceutical medicine and has a pharmacological effect. India has a long history of being heavily dependent for these raw materials on China due to one major reason i.e. Low manufacturing cost. But overdependence of APIs imports from China brought various liabilities to India including supply chain disruption and price hikes during pandemic, leading to shortage of various important APIs/KSMs. This COVID 19 widespread has solidly put the center of our country on being “Atma Nirbhar”. And this activity had brought out the strengths, market patterns and opportunities in five divisions counting Healthcare, which are basic from country’s point of view. In view of changing geo-political situation and recalibrated trade arrangement, it is crucial that India become self-reliant within the generation of APIs and KSMs, which is why decreasing the Import reliance for Active pharmaceutical ingredients (APIs) & Key starting materials (KSMs) particularly from china has been focused upon with the assistance of productive linked incentive scheme (PLIS) passed by Department of pharmaceuticals, Government of India to thrive Indian API industry. Hence, this review highlights the current state of Indian API industry, evaluates challenges, opportunities give suggestions for moving forward for self-sufficiency of APIs as well as centers on current regulatory prerequisites for Active pharmaceutical Ingredients.

Download Full-text

Digital tax: an instructive foreign experience

Russian Economic Journal ◽

10.33983/0130-9757-2020-4-69-87 ◽

2020 ◽

pp. 69-87

Author(s):

K.S. Teteryatnikov ◽

S.G. Каmolov ◽

D.A. Blashkina

Keyword(s):

Russian Federation ◽

High Tech ◽

Digital Products ◽

Tax Reforms ◽

Goods And Services ◽

Russian Economy ◽

Internet Users ◽

The Usa ◽

On Line ◽

The Russian Federation

The article is meant to analyze current problems and prospects for the development of effective tax policy as part of digital transformation of Russian economy. Introduction of a digital tax and the consequences of the digital tax reforms in the EU, the USA and OECD countries are highlighted. The necessity of qualitative transformation of the tax system of the Russian Federation in response to modern challenges is substantiated, taking into account the changes of the Tax Code of the Russian Federation adopted at the end of July 2020. The authors suggested their own concept of a digital tax and the prospects for its adoption in Russia, and consider it inappropriate to impose taxes on Internet users who do not use the Internet for business. Today, the main focus should be made on creating and testing effective technologies that allow on-line monitoring the tax basis of digital economy entities, taking into account the cross-border movement or use of digital products (goods and services). In addition, it would be extremely important to provide for a potential tax exemption for part of the profits of international ICT companies that are received on the territory of the Russian Federation and reinvested in joint with Russian companies projects in the high-tech for civil purposes area.

Download Full-text

Topical Analgesic Formulations: Following the Transdermal Treatment Paradigm Only?

Journal of Clinical and Medical Research ◽

10.37191/mapsci-2582-4333-1(3)-017 ◽

2019 ◽

Author(s):

Jan M Keppel Hesselink

Keyword(s):

Ad Hoc ◽

Active Pharmaceutical Ingredient ◽

Mechanisms Of Action ◽

Onset Of Action ◽

Good Tolerability ◽

Short Commentary ◽

Topical Analgesics ◽

The Usa ◽

Treatment Paradigm ◽

Topical Analgesic

Topical analgesics are regarded as new inroads to treat peripheral neuropathic pain, with a number of advantages over oral treatments. Topical treatment reduces systemic induced side-effects and have good tolerability, without problems of misuse or abuse, or dependency. Furthermore, the onset of action is fast, mostly within 30 minutes. The mechanism of action of topical analgesics is either via transdermal delivery of the analgesic, or via intradermal mechanisms of action. In the latter case, plasma levels of analgesics in the blood are absent or very low. This perspective is missing in the approach of the ad hoc committee of the National Academies of Sciences, Engineering, and Medicine in the USA, installed by the FDA. In this short commentary, we plead for a more comprehensive approach of topical analgesics, including those formulations which explicitly are not based on transdermal penetration of the active pharmaceutical ingredient, but on intradermal mechanisms of action.

Download Full-text