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Current regulatory requirements and practical approaches for stability analysis of pharmaceutical products: A comprehensive review

Sengupta P, Chatterjee B, Tekade RK

Int J Pharm, 2018 May 30;543(1-2):328-344.
PMID: 29635054 DOI: 10.1016/j.ijpharm.2018.04.007

Different regulatory guidelines recommend establishing stability profile of pharmaceuticals at the time of drug development. The expiry date, retesting period and storage conditions of active drugs or products are established through stability analysis. Several regulatory guidelines exist for stability testing of pharmaceuticals. Mostly, ICH stability guidelines are followed in practice. This guideline recommends to validate stability indicating method using forced degradation samples that contains all possible degradation impurities. ICH guidelines provide general recommendations for inclusion of stability indicating parameters in a stability testing protocol. However, those guidelines do not provide specific requirements and experimental methodology to be followed for stability studies. Due to this gap, often confusion arises in the scientific community in designing stability testing protocol. Therefore, significant variations are observed in reported literature in selection of stability indicating parameters. Procedural dissimilarity amongst reported stability studies is also evident. This review discusses the regulatory guidelines and procedures to follow in performing stability testing of pharmaceuticals. Scope of this review also includes recommendations on practical approaches for designing stability testing protocol to fulfill current regulatory requirements for drug substances and their formulations.

Matched MeSH terms: Chemistry, Pharmaceutical/legislation & jurisprudence*; Chemistry, Pharmaceutical/methods
Fulltext Designing and validating a new asian family scale

Ramli Musa, Mat Aris MA, Draman S, Abdullah K, Bujang MA

International Medical Journal Malaysia, 2015;14(2):23-28.
MyJurnal

All available family scales are designed for western countries and there is no validated
family scale which is specifically devised for Asian population. The difference in culture and family values warrants the formulation of a specific Asian family scale to cater the regional needs. The objectives are to devise and validate a new family scale and eventually to validate it for Malaysian population.

Matched MeSH terms: Chemistry, Pharmaceutical
Design and evaluation of a gastroretentive drug delivery system for metformin HCl using synthetic and semi-synthetic polymers

Meka VS, Gorajana A, Dharmanlingam SR, Kolapalli VR

Invest Clin, 2013 Dec;54(4):347-59.
PMID: 24502177

The aim of the present research was to prepare and evaluate a gastroretentive drug delivery system for metformin HCl, using synthetic and semi-synthetic polymers. The floating approach was applied for preparing gastroretentive tablets (GRT) and these tablets were manufactured by the direct compression method. The drug delivery system comprises of synthetic and semi-synthetic polymers such as polyethylene oxide and Carboxymethyl ethyl cellulose (CMEC) as release-retarding polymers. GRT were evaluated for physico-chemical properties like weight variation, hardness, assay friability, in vitro floating behaviour, swelling studies, in vitro dissolution studies and rate order kinetics. Based upon the drug release and floating properties, two formulations (MP04 & MC03) were selected as optimized formulations. The optimized formulations MP04 and MC03 followed zero order rate kinetics, with non-Fickian diffusion and first order rate kinetics with erosion mechanism, respectively. The optimized formulation was characterised with FTIR studies and it was observed that there was no interaction between the drug and polymers.

Matched MeSH terms: Chemistry, Pharmaceutical/methods
Thermal sintering: a novel technique in the design of gastroretentive floating tablets of propranolol HCl and its evaluation

Meka VS, Songa AS, Nali SR, Battu JR, Kukati L, Kolapalli VR

Invest Clin, 2012 Sep;53(3):223-36.
PMID: 23248967

The aim of the present investigation was to formulate thermally sintered floating tablets of propranolol HCl, and to study the effect of sintering conditions on drug release, as well as their in vitro buoyancy properties. A hydrophilic polymer, polyethylene oxide, was selected as a sintered polymer to retard the drug release. The formulations were prepared by a direct compression method and were evaluated by in vitro dissolution studies. The results showed that sintering temperature and time of exposure greatly influenced the buoyancy, as well as the dissolution properties. As the sintering temperature and time of exposure increased, floating lag time was found to be decreased, total floating time was increased and drug release was retarded. An optimized sintered formulation (sintering temperature 50 degrees C and time of exposure 4 h) was selected, based on their drug retarding properties. The optimized formulation was characterized with FTIR and DSC studies and no interaction was found between the drug and the polymer used.

Matched MeSH terms: Chemistry, Pharmaceutical/methods*
Phytochemical survey of Malaysian plants preliminary chemical and pharmacological screening

Nakanishi K, Sasaki S, Kiang AK, Goh J, Kakisawa H, Ohashi M, et al.

Chem Pharm Bull (Tokyo), 1965 Jul;13(7):882-90.
PMID: 5867816
Matched MeSH terms: Chemistry, Pharmaceutical*
Promises of Molecular Pharmaceutics in the Development of Novel Drug Delivery Formulations

Kumar P, Chaudhary B, Jain V, Baboota S, Shivanandy P, Alharbi KS, et al.

Curr Drug Deliv, 2023;20(9):1262-1274.
PMID: 36380413 DOI: 10.2174/1567201820666221114113637

Molecular pharmaceutics play a critical role in the drug delivery system, representing the direct interconnection of drug bioavailability with its molecular form. There is a diversity in the molecular structures by which it affects its properties, such as amorphous form, crystalline form, partialamorphous molecular dispersion, and disordered state. The active pharmaceutical ingredient (API) and the excipients utilized in the formulation process contain various divergent modes used in the formulation process. They include better formulations of any type to obtain good quality pharmaceutical products. This review reveals how the molecular states affect the API and are important in maintaining the quality of dosage forms. Furthermore, the physio-chemical properties of the components and various pharmaceutical approaches employed in the formulation of dosage forms are studied from the point of view of molecular pharmaceutics.

Matched MeSH terms: Chemistry, Pharmaceutical*
Fulltext Functionality of wet-granulated disintegrant in comparison to directly incorporated disintegrant in a poorly water-soluble tablet matrix

Veronica N, Lee ESM, Heng PWS, Liew CV

Int J Pharm, 2024 Aug 15;661:124467.
PMID: 39004293 DOI: 10.1016/j.ijpharm.2024.124467

Tablet disintegration is crucial for drug release and subsequent systemic absorption. Although factors affecting the disintegrant's functionality have been extensively studied, the impact of wet granulation on the performance of disintegrants in a poorly water-soluble matrix has received much less attention. In this study, the disintegrants, crospovidone (XPVP), croscarmellose sodium (CCS) and sodium starch glycolate (SSG), were wet-granulated with dibasic calcium phosphate dihydrate as the poorly water-soluble matrix and polyvinylpyrrolidone as the binder. The effect of wet granulation was studied by evaluating tablet tensile strength and disintegratability. Comparison between tablets with granulated or ungranulated disintegrants as well those without disintegrants were also made. Different formulations showed different degrees of sensitivity to changes in tablet tensile strength and disintegratability post-wet granulation. Tablet tensile strength decreased for tablets with granulated disintegrant XPVP or CCS, but to a smaller extent for SSG. While tablets with granulated XPVP or CCS had increased disintegration time, the increment was lesser than for SSG, suggesting that wet granulation impacted a swelling disintegrant more. The findings showed that tablets with wet-granulated disintegrant had altered the disintegrant's functionality. These findings could provide better insights into changes in the disintegrant's functionality after wet granulation.

Matched MeSH terms: Chemistry, Pharmaceutical/methods
QbD Assisted Systematic Review for Optimizing the Selection of PVP as a Ternary Substance in Enhancing the Complexation Efficiency of Cyclodextrins: a Pilot Study

Mulenga G, Alahmed TAA, Sami F, Majeed S, Ali MS, Le JLJ, et al.

AAPS PharmSciTech, 2024 Jun 11;25(5):134.
PMID: 38862663 DOI: 10.1208/s12249-024-02845-3

Inclusion complexes require higher concentration of Beta cyclodextrins (βCD) resulting in increased formulation bulk, toxicity, and production costs. This systematic review offers a comprehensive analysis using Quality by design (QbD) as a tool to predict potential applications of Polyvinylpyrrolidone (PVP) as a ternary substance to address issues of inclusion complexes. We reviewed 623 documents from 2013 to 2023 and Eighteen (18) research papers were selected for statistical and meta-analysis using the QbD concept to identify the most critical factors for selecting drugs and effect of PVP on inclusion complexes. The QbD analysis revealed that Molecular weight (MW), Partition coefficient (Log P), and the auxiliary substance ratio directly affected complexation efficiency (CE), thermodynamic stability in terms of Gibbs free energy (ΔG), and percent drug release. However, Stability constant (Ks) remained unaffected by any of these parameters. The results showed that low MW (250), median Log P (6), and a βCD: PVP ratio of 2:3 would result in higher CE, lower G, and improved drug release. PVP improves drug solubility, enhances delivery and therapeutic outcomes, and counteracts increased drug ionization due to decreased pH. In certain cases, its bulky nature and hydrogen bonding with CD molecules can form non-inclusion complexes. The findings of the study shows that there is potential molecular interaction between PVP and β-cyclodextrins, which possibly enhances the stability of inclusion complexes for drug with low MW and log P values less than 9. The systematic review shows a comprehensive methodology based on QbD offers a replicable template for future investigations into drug formulation research.

Matched MeSH terms: Chemistry, Pharmaceutical/methods
Small Molecules for Active Targeting in Cancer

Kue CS, Kamkaew A, Burgess K, Kiew LV, Chung LY, Lee HB

Med Res Rev, 2016 Apr;36(3):494-575.
PMID: 26992114 DOI: 10.1002/med.21387

For the purpose of this review, active targeting in cancer research encompasses strategies wherein a ligand for a cell surface receptor expressed on tumor cells is used to deliver a cytotoxic or imaging cargo. This area of research is more than two decades old, but in those 20 and more years, how many receptors have been studied extensively? What kinds of the ligands are used for active targeting? Are they mostly naturally occurring molecules such as folic acid, or synthetic substances developed in campaigns for medicinal chemistry efforts? This review outlines the most important receptor or ligand combinations that have been used in active targeting to answer these questions, and therefore to address the most important one of all: is research in active targeting affording diminishing returns, or is this an area for which the potential far exceeds progress made so far?

Matched MeSH terms: Chemistry, Pharmaceutical
Fulltext On the integral solutions of the diophantine equation x4 + y4 = z3

Ismail, S., Mohd Atan, K.A.

Pertanika Journal of Science & Technology, 2013;21(1):119-126.
MyJurnal

This paper is concerned with the existence, types and the cardinality of the integral solutions for
diophantine equation
4 4 3
x y z + = where x , y and z are integers. The aim of this paper was to
develop methods to be used in finding all solutions to this equation. Results of the study show the
existence of infinitely many solutions to this type of diophantine equation in the ring of integers
for both cases, x y = and x y ¹ . For the case when x y = , the form of solutions is given by
3 3 4
( , , ) (4 , 4 ,8 ) x y z n n n = , while for the case when x y ¹ , the form of solutions is given by
3 1 3 1 4 1
( , , ) ( , , )
k k k
x y z un vn n
- - -
= . The main result obtained is a formulation of a generalized method to find
all the solutions for both types of diophantine equations.

Matched MeSH terms: Chemistry, Pharmaceutical
Advances and challenges in developing andrographolide and its analogues as cancer therapeutic agents

Soo HL, Quah SY, Sulaiman I, Sagineedu SR, Lim JCW, Stanslas J

Drug Discov Today, 2019 09;24(9):1890-1898.
PMID: 31154065 DOI: 10.1016/j.drudis.2019.05.017

Andrographolide (AGP), a naturally occurring bioactive compound, has been investigated as a lead compound in cancer drug development. Its multidimensional therapeutic effects have raised interest among medicinal chemists, which has led to extensive structural modification of the compound, resulting in analogues with improved pharmacological and pharmaceutical properties. Nevertheless, the analogues with the improved properties need to be rigorously studied to identify drug-like lead compounds. We scrutinised articles published from 2012 to 2018, to objectively provide opinions on the mechanisms of action of AGP and its analogues, as well as their potential as viable anticancer drugs. Preclinical and clinical data, along with the extensive medicinal chemistry efforts, indicate the compounds are potential anticancer agents with specific value in treating recalcitrant cancers such as pancreatic and lung cancers.

Matched MeSH terms: Chemistry, Pharmaceutical
Cavitation technology - a greener processing technique for the generation of pharmaceutical nanoemulsions

Sivakumar M, Tang SY, Tan KW

Ultrason Sonochem, 2014 Nov;21(6):2069-83.
PMID: 24755340 DOI: 10.1016/j.ultsonch.2014.03.025

Novel nanoemulsion-based drug delivery systems (DDS) have been proposed as alternative and effective approach for the delivery of various types of poorly water-soluble drugs in the last decade. This nanoformulation strategy significantly improves the cell uptake and bioavailability of numerous hydrophobic drugs by increasing their solubility and dissolution rate, maintaining drug concentration within the therapeutic range by controlling the drug release rate, and reducing systemic side effects by targeting to specific disease site, thus offering a better patient compliance. To date, cavitation technology has emerged to be an energy-efficient and promising technique to generate such nanoscale emulsions encapsulating a variety of highly potent pharmaceutical agents that are water-insoluble. The micro-turbulent implosions of cavitation bubbles tear-off primary giant oily emulsion droplets to nano-scale, spontaneously leading to the formation of highly uniform drug contained nanodroplets. A substantial body of recent literatures in the field of nanoemulsions suggests that cavitation is a facile, cost-reducing yet safer generation tool, remarkably highlighting its industrial commercial viability in the development of designing novel nanocarriers or enhancing the properties of existing pharmaceutical products. In this review, the fundamentals of nanoemulsion and the principles involved in their formation are presented. The underlying mechanisms in the generation of pharmaceutical nanoemulsion under acoustic field as well as the advantages of using cavitation compared to the conventional techniques are also highlighted. This review focuses on recent nanoemulsion-based DDS development and how cavitation through ultrasound and hydrodynamic means is useful to generate the pharmaceutical grade nanoemulsions including the complex double or submicron multiple emulsions.

Matched MeSH terms: Chemistry, Pharmaceutical/methods*
Fulltext The use of umbelliferone in the synthesis of new heterocyclic compounds

Al-Amiery AA, Musa AY, Kadhum AA, Mohamad AB

Molecules, 2011 Aug 10;16(8):6833-43.
PMID: 21832973 DOI: 10.3390/molecules16086833

New coumarin derivatives, namely 7-[(5-amino-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one, 5-[(2-oxo-2H-chromen-7-yloxy)methyl]-1,3,4-thiadiazol-2(3H)-one, 2-[2-(2-oxo-2H-chromen-7-yloxy)acetyl]-N-phenylhydrazinecarbothioamide, 7-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one and 7-[(5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy]-2H-chromen-2-one were prepared starting from the natural compound umbelliferone. The newly synthesized compounds were characterized by elemental analysis and spectral studies (IR, ¹H-NMR and ¹³C-NMR).

Matched MeSH terms: Chemistry, Pharmaceutical/methods*
Use of microwave in processing of drug delivery systems

Wong TW

Curr Drug Deliv, 2008 Apr;5(2):77-84.
PMID: 18393808

Microwave has received a widespread application in pharmaceuticals and food processing, microbial sterilization, biomedical therapy, scientific and biomedical analysis, as well as, drug synthesis. This paper reviews the basis of application of microwave to prepare pharmaceutical dosage forms such as agglomerates, gel beads, microspheres, nanomatrix, solid dispersion, tablets and film coat. The microwave could induce drying, polymeric crosslinkages as well as drug-polymer interaction, and modify the structure of drug crystallites via its effects of heating and/or electromagnetic field on the dosage forms. The use of microwave opens a new approach to control the physicochemical properties and drug delivery profiles of pharmaceutical dosage forms without the need for excessive heat, lengthy process or toxic reactants. Alternatively, the microwave can be utilized to process excipients prior to their use in the formulation of drug delivery systems. The intended release characteristics of drugs in dosage forms can be met through modifying the physicochemical properties of excipients using the microwave.

Matched MeSH terms: Chemistry, Pharmaceutical/methods
Alkaloids of Kopsia

Kam TS, Lim KH

Alkaloids Chem Biol, 2008;66:1-111.
PMID: 19025097
Matched MeSH terms: Chemistry, Pharmaceutical/methods
Interfacial elastic relaxation during the ejection of bi-layered tablets

Anuar MS, Briscoe BJ

Int J Pharm, 2010 Mar 15;387(1-2):42-7.
PMID: 19963050 DOI: 10.1016/j.ijpharm.2009.11.031

The predilection of a bi-layered tablet to fail in the interface region after its initial formation in the compaction process reduces its practicality as a choice for controlled release solid drug delivery system. Hence, a fundamental appreciation of the governing mechanism that causes the weakening of the interfacial bonds within the bi-layered tablet is crucial in order to improve the overall bi-layered tablet mechanical integrity. This work has shown that the occurrence of the elastic relaxation in the interface region during the ejection stage of the compaction process decreases with the increase in the bi-layered tablet interface strength. This is believed to be due to the increase in the plastic bonding in the interface region. The tablet diametrical elastic relaxation affects the tablet height elastic relaxation, where the impediment of the tablet height expansion is observed when the interface region experiences a diametrical expansion.

Matched MeSH terms: Chemistry, Pharmaceutical/methods
Functional properties of dually modified sago starch/κ-carrageenan films: An alternative to gelatin in pharmaceutical capsules

Oladzadabbasabadi N, Ebadi S, Mohammadi Nafchi A, Karim AA, Kiahosseini SR

Carbohydr Polym, 2017 Mar 15;160:43-51.
PMID: 28115099 DOI: 10.1016/j.carbpol.2016.12.042

The aim of this study was development a composite film based on sago starch and κ-carrageenan to find a gelatin alternative in the pharmaceutical capsules processing. Hydrolyzed-Hydroxypropylated (dually modified) sago starch was mixed with κ-carrageenan (0.25, 0.5, 0.75, and 1%). The drying kinetics, thermomechanical, physicochemical, and barrier properties of composite films were estimated and compared with bovine gelatin. Results show that drying kinetics and mechanical properties of the composite films were comparable to those of gelatin. The water vapor permeability and moisture content of the composite films were lower than those of gelatin. The solubility of the composite films was higher than that of gelatin, and the composite films were more stable at higher relative humidity than were the gelatin films. These results show that dually modified sago starch in combination with κ-carrageenan has properties similar to those of gelatin, thus proposed system can be used in pharmaceutical capsules processes.

Matched MeSH terms: Chemistry, Pharmaceutical*
Comparison of Disintegrant-addition Methods on the Compounding of Orodispersible Tablets

Mahesparan VA, Bin Abd Razak FS, Ming LC, Uddin AH, Sarker MZI, Bin LK

Int J Pharm Compd, 2020 3 21;24(2):148-155.
PMID: 32196477

Orodispersible tablets disintegrate rapidly (within 3 minutes) in the oral cavity and release the medicament before swallowing. The mode of disintegrant addition might affect the properties of orodispersible tablets. The objective of this study was to formulate and evaluate orodispersible tablets by studying different modes of disintegration addition with varying concentrations of disintegrants. The wet granulation method was used to produce the orodispersible tablets. Two methods of disintegration addition were compared (i.e., intragranular, extragranular). Three disintegrants (i.e., cornstarch, sodium starch glycolate, crospovidone) were used at three levels (5%, 10%, and 15%) in the study. The formulations were tested for the powder flowability (angle of repose) and characterized physically (hardness, weight, thickness, friability, disintegration time). The mangosteen pericarp extract was used as a model active pharmaceutical ingredient to be incorporated into the optimum formulation. It was observed that the extragranular method produced granules with better flowability compared to that of the intragranular method. Crospovidone was found as the most efficient disintegrant among the three. The optimum formulation selected was one with the highest concentration of crospovidone (15%), which showed the fastest disintegration time. The mode of disintegrant addition into the orodispersible tablets formulation was found to show a marked difference in the disintegration, as well as other physical characteristics of the orodispersible tablets where the extragranular mode of addition showed better property, which caused the orodispersible tablets to disintegrate the fastest.

Matched MeSH terms: Chemistry, Pharmaceutical/methods
Fulltext Optimization of Processing Parameters of Nanoemulsion Containing Aripiprazole Using Response Surface Methodology

Samiun WS, Ashari SE, Salim N, Ahmad S

Int J Nanomedicine, 2020;15:1585-1594.
PMID: 32210553 DOI: 10.2147/IJN.S198914

BACKGROUND: Aripiprazole, which is a quinolinone derivative, has been widely used to treat schizophrenia, major depressive disorder, and bipolar disorder.
PURPOSE: A Central Composite Rotatable Design (CCRD) of Response Surface Methodology (RSM) was used purposely to optimize process parameters conditions for formulating nanoemulsion containing aripiprazole using high emulsification methods.
METHODS: This design is used to investigate the influences of four independent variables (overhead stirring time (A), shear rate (B), shear time (C), and the cycle of high-pressure homogenizer (D)) on the response variable namely, a droplet size (Y) of nanoemulsion containing aripiprazole.
RESULTS: The optimum conditions suggested by the predicted model were: 120 min of overhead stirring time, 15 min of high shear homogenizer time, 4400 rpm of high shear homogenizer rate and 11 cycles of high-pressure homogenizer, giving a desirable droplet size of nanoemulsion containing aripiprazole of 64.52 nm for experimental value and 62.59 nm for predicted value. The analysis of variance (ANOVA) showed the quadratic polynomial fitted the experimental values with F-value (9.53), a low p-value (0.0003) and a non-significant lack of-fit. It proved that the models were adequate to predict the relevance response. The optimized formulation with a viscosity value of 3.72 mPa.s and pH value of 7.4 showed good osmolality value (297 mOsm/kg) and remained stable for three months in three different temperatures (4°C, 25°C, and 45°C).
CONCLUSION: This proven that response surface methodology is an efficient tool to produce desirable droplet size of nanoemulsion containing aripiprazole for parenteral delivery application.

Matched MeSH terms: Chemistry, Pharmaceutical/methods
Understanding the Roles of Excipients in Moisture Management in Solid Dosage Forms

Veronica N, Heng PWS, Liew CV

Mol Pharm, 2024 May 06;21(5):2484-2500.
PMID: 38647432 DOI: 10.1021/acs.molpharmaceut.4c00031

Excipients are ubiquitous in pharmaceutical products, and often, they can also play a critical role in maintaining product quality. For a product containing a moisture-sensitive drug, moisture can be deleterious to the product stability during storage. Therefore, using excipients that interact with moisture in situ can potentially alleviate product stability issues. In this study, the interactive behavior of starch with moisture was augmented by coprocessing maize starch with sodium chloride (NaCl) or magnesium nitrate hexahydrate [Mg(NO3)2·6H2O] at different concentrations (5 and 10%, w/w). The effect of the formulation on drug stability was assessed through the degradation of acetylsalicylic acid, which was used as the model drug. The results showed that coprocessing of the starch with either NaCl or Mg(NO3)2·6H2O impacted the number of water molecule binding sites on the starch and how the sorbed moisture was distributed. The coprocessed excipients also resulted in lower drug degradation and lesser changes in tablet tensile strength during post-compaction storage. However, corresponding tablet formulations containing physical mixtures of starch and salts did not yield promising outcomes. This study demonstrated the advantageous concomitant use of common excipients by coprocessing to synergistically mitigate the adverse effects of moisture and promote product stability when formulating a moisture-sensitive drug. In addition, the findings could help to improve the understanding of moisture-excipient interactions and allow for the judicious choice of excipients when designing formulations containing moisture-sensitive drugs.

Matched MeSH terms: Chemistry, Pharmaceutical/methods

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