Enhancing the stability of active pharmaceutical ingredients by cocrystal strategy

Stability Problems ◽

The Past ◽

Scant Attention ◽

Cocrystallization has been recognized as one of the most successful approaches to address stability problems of active pharmaceutical ingredients (APIs) in the past few decades. However, scant attention has been...

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics

Pharmaceutics ◽

10.3390/pharmaceutics12020195 ◽

2020 ◽

Vol 12 (2) ◽

pp. 195

Author(s):

Ana Santoveña-Estévez ◽

Javier Suárez-González ◽

Amor R. Cáceres-Pérez ◽

Zuleima Ruiz-Noda ◽

Sara Machado-Rodríguez ◽

...

Keyword(s):

Ascorbic Acid ◽

Stability Study ◽

Adherence To Treatment ◽

Antituberculosis Treatment ◽

Maximum Stability ◽

Ph Conditions ◽

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) Methods: The active pharmaceutical ingredients stability under in vitro paediatric digestive pH conditions have been checked. The samples were studied as individual or fixed combined paediatric dosages to determine the pH of maximum stability. The use of hydroxypropyl-β-cyclodextrin to improve Rifampicin solubility and the use of ascorbic acid to increase the stability of the formulation have been studied. (3) Results: Maximum stability of combined doses was determined at pH 7.4, and maximum complexation at pH 8.0. Taking this into account, formulations presented the minimum dose of two active pharmaceutical ingredients dissolved. The addition of ascorbic acid at 0.1% w/v enables the detection of a higher remaining quantity of both drugs after three days of storage at 5 °C. (4) Conclusions: a formulation which combines the minimum paediatric dosages dissolved recommended by WHO for Isoniazid and Rifampicin has been developed. Future assays are needed to prolong the stability of the formulation with the aim of incorporating Pyrazinamide to the solution.

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 ◽

Statistical Associating Fluid Theory ◽

Soluble Solid ◽

Fluid Theory ◽

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.

How to Achieve High Encapsulation Efficiencies for Macromolecular and Sensitive APIs in Liposomes

Pharmaceutics ◽

10.3390/pharmaceutics13050691 ◽

2021 ◽

Vol 13 (5) ◽

pp. 691

Author(s):

Kirsten Ullmann ◽

Gero Leneweit ◽

Hermann Nirschl

Keyword(s):

Bovine Serum Albumin ◽

Serum Albumin ◽

Bovine Serum ◽

Encapsulation Efficiency ◽

Bending Modulus ◽

Vis Spectroscopy ◽

The Stability ◽

Very High

This research highlights the capacity of a newly introduced centrifugation process to form liposomes from water-in-fluorocarbon nano-emulsions stabilized with phospholipids to incorporate macromolecular and sensitive active pharmaceutical ingredients (API). The encapsulation efficiency of the produced liposomes, incorporating fluorescein-sodium, bovine serum albumin and fluorecein isothiocyanate dextran as model APIs, is determined by applying Vivaspin® centrifugation filtration and quantified by UV-Vis spectroscopy. It was found that higher densities of the fluorocarbons used as the hydrophobic phase enable a higher encapsulation efficiency and that an efficiency of up to 98% is possible depending on the used phospholipid. Among the engineering aspects of the process, a comparison between different membrane substances was performed. Efficiency increases with a higher phospholipid concentration but decreases with the addition of cholesterol. Due to the higher bending modulus, liposome formation is slowed down by cholesterol during liposome closure leading to a greater leakage of the model API. The encapsulation of bovine serum albumin and dextran, both investigated under different osmotic conditions, shows that an efflux negatively affects the encapsulation efficiency while an influx increases the stability. Overall, the process shows the potential for a very high encapsulation efficiency for macromolecules and future pharmaceutical applications.

Compatibility of Different Formulations in Pentravan® and Pentravan® Plus for Transdermal Drug Delivery

Scientia Pharmaceutica ◽

10.3390/scipharm89040051 ◽

2021 ◽

Vol 89 (4) ◽

pp. 51

Author(s):

Hudson Polonini ◽

Sarah Taylor ◽

Clark Zander

Keyword(s):

Vitamin D3 ◽

Transdermal Delivery ◽

Scientific Community ◽

Therapeutic Benefit ◽

Low Concentrations ◽

The Stability ◽

Potential Therapeutic Benefit ◽

Metformin Hcl

The potential therapeutic benefit of transdermal delivery systems for some active pharmaceutical ingredients (APIs) has been well-established for decades within the scientific community. However, together with the clinical efficacy, there is the need for an evaluation of the stability of such APIs in bases with known transdermal capabilities, which is necessary to provide the compounding pharmacist with confidence when providing transdermal products. In this study, the stability of danazol, metformin HCl, and resveratrol as individual ingredients, as well as metformin HCl, resveratrol, and Vitamin D3 in combinations at bracketed high and low concentrations, were evaluated over a period of 6 months, using a ready-to-use transdermal vehicle for compounding pharmacies (Pentravan® or Pentravan® Plus). The five formulations tested (F1: Danazol 50 mg/g + MiodesinTM 85 mg/g in Pentravan®, F2: Metformin HCl 200 mg/g in Pentravan®, F3: Resveratrol 200 mg/g in Pentravan®, F4: Metformin HCl 100 mg/g + Resveratrol 100 mg/g + Vitamin D3 5000 IU in Pentravan®, and F5: Metformin HCl 200 mg/g + Resveratrol 200 mg/g + Vitamin D3 5000 IU in Pentravan® Plus) presented a beyond-use date of at least 6 months, presenting high convenience for the compounding pharmacies.

Main group mechanochemistry

Beilstein Journal of Organic Chemistry ◽

10.3762/bjoc.13.204 ◽

2017 ◽

Vol 13 ◽

pp. 2068-2077 ◽

Cited By ~ 28

Author(s):

Agota A Gečiauskaitė ◽

Felipe García

Keyword(s):

Metal Oxides ◽

Organic Compounds ◽

Coordination Compounds ◽

Short Review ◽

Main Group ◽

Organometallic Complexes ◽

The Past ◽

Synthetic Routes

Over the past decade, mechanochemistry has emerged as a powerful methodology in the search for sustainable alternatives to conventional solvent-based synthetic routes. Mechanochemistry has already been successfully applied to the synthesis of active pharmaceutical ingredients (APIs), organic compounds, metal oxides, coordination compounds and organometallic complexes. In the main group arena, examples of synthetic mechanochemical methodologies, whilst still relatively sporadic, are on the rise. This short review provides an overview of recent advances and achievements in this area that further validate mechanochemistry as a credible alternative to solution-based methods for the synthesis of main group compounds and frameworks.

The effect of polymorphism on active pharmaceutical ingredients: A review

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11i2.2044 ◽

2020 ◽

Vol 11 (2) ◽

pp. 1621-1630

Author(s):

Ahmad Ainurofiq ◽

Kezia Esther Dinda ◽

Maya Widia Pangestika ◽

Ulia Himawati ◽

Wening Dyah Wardhani ◽

...

Keyword(s):

Production Process ◽

Chemical Properties ◽

Crystal Form ◽

Pharmaceutical Products ◽

Polymorphic Form ◽

The Stability ◽

Main Components ◽

Crystalline Forms

Active pharmaceutical ingredients (API) are the main components in the production process of pharmaceutical products. If the API has a good quality, then it will lead to good pharmaceutical products. API consists of more than one different crystal form which, then forms a polymorph through the process of polymorphism. Until now, API polymorphism is still a big challenge in the pharmaceutical industry. That is because the nature of polymorphism is difficult to predict. One of them is by crystallizing molecules in one or many crystalline forms or combining with other molecules to form stable co-crystal. This process will lead to several polymorph forms of one certain API. Sometimes, these forms will have characteristics that differ one to another. Each polymorph has different mechanical, physical, thermal, and chemical properties that will affect the solubility, dissolution, bioavailability, stability, bioequivalence, and manufacturing of the API. Therefore to know the nature of an API, it is necessary to characterize the polymorphic form of the API before. If the form is not incompatible with the formulation, it can cause a failure in the production process. This review will discuss the effect of polymorphism on the physicochemical properties of API. It is hoped that this review can become the basis for improving the stability and effectiveness of pharmaceutical products.

Comment on “Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs” by S. Aitipamula, P. S. Chow and R. B. H. Tan, CrystEngComm, 2009, 11, 1823

CrystEngComm ◽

10.1039/c7ce01448a ◽

2018 ◽

Vol 20 (3) ◽

pp. 370-372 ◽

Cited By ~ 1

Author(s):

Łukasz Szeleszczuk ◽

Dariusz Maciej Pisklak ◽

Monika Zielińska-Pisklak

Keyword(s):

Detailed Analysis ◽

Combination Drugs ◽

Pharmaceutical Cocrystal ◽

This is a commentary on a paper by S. Aitipamula et al. (CrystEngComm, 2009, 11, 1823–1827) on the detailed analysis of the stability of trimorphic cocrystals.

Reversed-Phase High Performance Liquid Chromatographic Analysis of Three First Line Anti-Tuberculosis Drugs

Revista de Chimie ◽

10.37358/rc.18.12.6799 ◽

2019 ◽

Vol 69 (12) ◽

pp. 3590-3592

Author(s):

Nela Bibire ◽

Romeo Iulian Olariu ◽

Luminita Agoroaei ◽

Madalina Vieriu ◽

Alina Diana Panainte ◽

...

Keyword(s):

High Performance ◽

Biological Fluids ◽

Gradient Elution ◽

High Performance Liquid Chromatographic ◽

Reversed Phase ◽

Assay Method ◽

First Line ◽

Liquid Chromatographic

Active pharmaceutical ingredients such as isoniazid, pyrazinamide and rifampicin are among the most important first-line anti-tuberculosis drugs. A simple, rapid and sensitive reversed phase-high performance liquid chromatographic assay method for the simultaneous determination of isoniazid, pyrazinamide and rifampicin has been developed. Separation of the interest compounds was achieved in a 10 min chromatographic run in gradient elution mode on a Zorbax SB-C18 stainless steel column (150 � 4 mm, 5 mm) using a guard column containing the same stationary phase. The gradient elution was carried out with a mobile phase of 10% CH3CN aqueous solution for channel A and 50% CH3CN in pH = 6.8 phosphate buffer (20 mM), to which 1.5 mL triethylamine were added for channel B. Quantification of the analyzed substances was carried out spectrophotometrically at 269 nm. Detection limits of 0.48 mg/L for isoniazid, 0.52 mg/L for pyrazinamide and 0.48 mg/L for rifampicin were established for the developed assay method. The present work showed that the proposed analysis method was advantageous for simple and rapid analysis of the active pharmaceutical ingredients in pharmaceuticals and biological fluids.

Stability and Folding of the Unusually Stable Hemoglobin from Synechocystis is Subtly Optimized and Dependent on the Key Heme Pocket Residues.

Protein and Peptide Letters ◽

10.2174/0929866527666200613220245 ◽

2020 ◽

Vol 27 ◽

Author(s):

Sheetal Uppal ◽

Mohd. Asim Khan ◽

Suman Kundu

Keyword(s):

Molten Globule ◽

Life Forms ◽

Model System ◽

Heme Pocket ◽

The Past ◽

Specific Manner ◽

Delivery Vehicles ◽

The Stability ◽

Key Residues ◽

Synechocystis Sp

Aims: The aim of our study is to understand the biophysical traits that govern the stability and folding of Synechocystis hemoglobin, a unique cyanobacterial globin that displays unusual traits not observed in any of the other globins discovered so far. Background: For the past few decades, classical hemoglobins such as vertebrate hemoglobin and myoglobin have been extensively studied to unravel the stability and folding mechanisms of hemoglobins. However, the expanding wealth of hemoglobins identified in all life forms with novel properties, like heme coordination chemistry and globin fold, have added complexity and challenges to the understanding of hemoglobin stability, which has not been adequately addressed. Here, we explored the unique truncated and hexacoordinate hemoglobin from the freshwater cyanobacterium Synechocystis sp. PCC 6803 known as “Synechocystis hemoglobin (SynHb)”. The “three histidines” linkages to heme are novel to this cyanobacterial hemoglobin. Objective: Mutational studies were employed to decipher the residues within the heme pocket that dictate the stability and folding of SynHb. Methods: Site-directed mutants of SynHb were generated and analyzed using a repertoire of spectroscopic and calorimetric tools. Result: The results revealed that the heme was stably associated to the protein under all denaturing conditions with His117 playing the anchoring role. The studies also highlighted the possibility of existence of a “molten globule” like intermediate at acidic pH in this exceptionally thermostable globin. His117 and other key residues in the heme pocket play an indispensable role in imparting significant polypeptide stability. Conclusion: Synechocystis hemoglobin presents an important model system for investigations of protein folding and stability in general. The heme pocket residues influenced the folding and stability of SynHb in a very subtle and specific manner and may have been optimized to make this Hb the most stable known as of date. Other: The knowledge gained hereby about the influence of heme pocket amino acid side chains on stability and expression is currently being utilized to improve the stability of recombinant human Hbs for efficient use as oxygen delivery vehicles.

Anti-corruption in History

10.1093/oso/9780198809975.001.0001 ◽

2017 ◽

Keyword(s):

Financial Institutions ◽

Global Media ◽

Policy Makers ◽

The Past ◽

Human Wellbeing ◽

Modern Period ◽

Legitimate Power ◽

Wide Range ◽

Scant Attention ◽

Over Time

Anticorruption in History is the first major collection of case studies on how past societies and polities, in and beyond Europe, defined legitimate power in terms of fighting corruption and designed specific mechanisms to pursue that agenda. It is a timely book: corruption is widely seen today as a major problem, undermining trust in government, financial institutions, economic efficiency, the principle of equality before the law and human wellbeing in general. Corruption, in short, is a major hurdle on the “path to Denmark”—a feted blueprint for stable and successful statebuilding. The resonance of this view explains why efforts to promote anticorruption policies have proliferated in recent years. But while the subjects of corruption and anticorruption have captured the attention of politicians, scholars, NGOs and the global media, scant attention has been paid to the link between corruption and the change of anticorruption policies over time and place. Such a historical approach could help explain major moments of change in the past as well as reasons for the success and failure of specific anticorruption policies and their relation to a country’s image (of itself or as construed from outside) as being more or less corrupt. It is precisely this scholarly lacuna that the present volume intends to begin to fill. A wide range of historical contexts are addressed, ranging from the ancient to the modern period, with specific insights for policy makers offered throughout.