Pharmaceutical Incompatibilities Research Articles

Conformity of Package Inserts Information to Regulatory Requirements

ABSTRACT Background: Accurate and reliable information regarding drugs is essential for safe and effective use of drugs. It is not possible for the clinician to refer research articles every time for complete updates. In such situations, package inserts (PIs) form an authentic information for the doctor and patient. The study was intended to assess the information completeness and precision of PIs using the criteria laid down by, sections 6.2 and 6.3 of Schedule D (II), Schedule Y of Drugs and Cosmetic Act (1940) and Rules (1945). Materials and Methods: PIs of different formulations were collected from various departments, and also local and regional chemists. The information adequacy was done by 25 checklist proposed by the Indian Drug and Cosmetic Act (1940) and Rules, 1945 under sections 6.2 and 6.3 of Schedule D and Schedule Y. A score of “1” was given, if information was present, and “0” if there was no information. Information adequacy scores also calculated. Results: A total of 207 PIs were analyzed. Majority of PIs belong Grade B category of drug information (174). Generic name, composition, posology and method of administration, undesirable effects, contraindications, drug interactions, special precautions, legibility, storage and contraindications during pregnancy and breast feeding were mentioned by nearly all. Gaps were observed in handling instructions, influence on person’s self-driving and machinery operation capabilities, pharmaceutical incompatibilities, shelf life, excipients and Pharmacokinetic and dynamic information not updated regularly. Conclusion: The current study shows that there is still inadequacy of particulars regarding drug information. Hence, it is essential to establish proper uniform standards for the currently available PIs. An absolute and flawless PI should provide complete information. This requires continuous and constant effort from manufacturer and regulatory authorities to promote safe and rational use of medicines.

Pharmaceutical Incompatibility of Lubricating Gel Formulation Reduces Antibacterial Activity of Chlorhexidine Gluconate: In Vitro Study in Northern Thailand.

Chlorhexidine gluconate (CHG) is a cationic disinfectant. The positive charge of CHG molecules binds to phospholipid’s negative charge in bacterial cell walls, causing membrane disruption. The in vitro kinetic physical, chemical and biological incompatibilities of nine lubricating gels with 1% w/v CHG were investigated. Five containing anionic thickener, two containing nonionic thickener, and two containing cationic thickener were collected from hospitals in northern Thailand. All the anionic and nonionic lubricating gels significantly reduced (p < 0.05) the CHG amount after 5 min of exposure time from 12.54% to 54.99%, respectively. In contrast, the amount of CHG exposed with cationic lubricating gels was maintained. Antibacterial activity was significantly reduced to a 1.17–4.33 log10 reduction for Staphylococcus aureus ATCC25923 and a 1.07–3.52 log10 reduction for Escherichia coli ATCC25922 after 5 min exposure to all anionic and nonionic lubricating gels. In contrast, the two cationic lubricating gels maintained the antibacterial activity of the CHG solution (5.69 ± 0.14 and 5.45 ± 0.17 log10 reduction). The results suggest that anionic and nonionic thickeners in lubricating gel formulations may neutralize the positive charge and reduce the antibacterial activity of CHG, reducing its effectiveness as a disinfectant.

Physicochemical compatibility studies of triclosan and flurbiprofen with excipients of pharmaceutical formulation using binary, ternary, and multi-combination approach

BackgroundThe aim of the study was to evaluate the suitability of triclosan (TCS) and flurbiprofen (FLB) with poly-ε-caprolactone (PCL), chitosan (CS), and Kolliphor® P188 (KP) for possible application in the design of nano-formulations.ResultsDifferential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM) revealed the physical characteristics of the various sample compositions without any apparent interaction. The Fourier transform infrared spectroscopy (FTIR)’s spectra of the physical mixtures showed their characteristic absorption bands with broadening and overlapping of bands in some instances, but no appearance of new bands was observed.ConclusionThe study revealed the physical form stability of the evaluated components after the storage period and lack of definite pharmaceutical incompatibility between them. Thus, the selected drugs and excipients could be used for the development of pharmaceutical nano-formulations.

The use of machine learning methods in the development of nasal dosage forms with cerebroprotective action

In order to save resource of active pharmaceutical ingredients and excipients, in the early stages of research, when planning an experiment, it is advisable to use data of the predicted and experimental physicochemical properties stored in different aggregation databases. The information found will reduce the time for composition development and for technology processing. However, the variety of active compounds characteristics and excipients is not always reflected in these services. Recently, machine learning models have been widely used in various scientific fields; they allow to obtain predictions with high reliability. Given the above, it is relevant and promising to develop models of machine learning to predict the presence of pharmaceutical incompatibilities in the formulation of nasal dosage forms. The aim of the study is to develop models of machine learning for in silico forecast of the rational composition of nasal dosage forms with cerebroprotective action. Materials and methods. A dataset, containing data on compounds (active and auxiliary) and characteristics on the presence or absence of interaction (pharmaceutical incompatibility), was used as material. Training datasets were filled by content analysis of PubMed library data (pubmed.ncbi.nlm.nih.gov) manually, by keywords “pharmaceutical incompatibilities”, “physico-chemical compatibility”, “incompatible excipients”) for the last 10 years. The resulting dataset comprises 1185 lines. The methods employed were a set of methods for binary classification of machine learning (pycaret.org) using the programming language Python 3.8 (python.org) in the package management environment Miniconda (conda.io). Pipeline programming was performed using Jupyter notebook package (jupyter.org). The generation of MACCS (Molecular ACCess System keys) in the training dataset was performed using RDKit package (rdkit.org). Specifications of the simplified representation of molecules in the input line (SMILES), in automatic mode, were searched using PubChem service (pubchem.ncbi.nlm.nih.gov). Results. The obtained data allowed to choose two perspective models of machine learning of binary classification, whose quality was checked on a dataset for verification. Statistical evaluations of the selected models indicate a high probability of in silico prognosis for the presence or absence of pharmaceutical incompatibilities in the development of nasal formulations of cerebroprotective dosage forms. They are posted on the web server of the expert system ExpSys Nasalia (nasalia.zsmu.zp.ua) in the calculations section. Conclusions. As a result of our research, we have developed machine learning models for in silico prediction of the rational composition of nasal dosage forms with cerebroprotective action. Confirmation of the quality of the pharmaceutical incompatibilities prediction, using the developed models, is checked on a dataset for check. The statistical indicators of the tree_blender (AUC 0.9521, F1 0.9747, MCC 0.9094) and boost_blender (AUC 0.9593, F1 0.9821, MCC 0.9352) models were obtained. The use of machine learning models in pharmaceutical development will contribute to resource conservation and optimization of the composition of the formulation.

Czy w dzisiejszych czasach proste obserwacje mogą jeszcze znacząco zmieniać postrzeganie podstawowych zjawisk? Przypadek cieczy eutektycznych

Can Simple Observations Today Still Significantly Change the Perception of Basic Phenomena? The Case of Eutectic Solvents The article presents a case study in which a simple, practical observation significantly changed the perception of basic phenomena regarding the mechanism of cell functioning, and thus was able to change the existing theory. This observation drew attention to the fact that the extract obtained from the dry plant substance with the use of pure alcohol, after distilling off the solvent, does not give a dry concentrated extract, and the viscous residue cannot be dried by distillation. This is a phenomenon that practically every phytochemist has encountered since the inception of this field of knowledge. It turned out that the explanation for the described phenomenon is the presence of eutectic solvents. Eutectic solvents are formed by mixing specific solid components, which liquefy without the addition of solvents, thanks to a significant lowering of the melting point of the mixture compared to the melting points of the starting materials. Although more than a hundred years have passed since the description of the above phenomenon, in the field of natural sciences, eutectic solvents have been treated as a curiosity for a long time, while in medical sciences – and more specifically in pharmacy – they were considered an inconvenience causing pharmaceutical incompatibilities. In fact, they are essential for the functioning of cells, enabling plants to develop frost resistance, being responsible for the ability to cryopreserve animal tissues, or allowing the dissolution of substances which are otherwise insoluble inside the cell in either the lipid layer or the aqueous part of the cell juice. The described discovery, made in 2011, allowed for a leap improvement in the understanding of the functioning of living cells.

Information adequacy of medicine package inserts in India: A critical evaluation.

Objectives:Package inserts (PIs) are used by physicians and other health-care providers as ready source of approved prescribing information. In India, they are subject to statutory regulations that specify the information to be provided under various headings. Uniformity of PIs with optimal level of information is desirable, the absence of which may lead to medication errors. This observational study aimed to evaluate the information adequacy and accuracy of PIs available in the Indian market.Materials and Methods:PIs of drugs marketed in India, and approved by United States Food and Drug Administration, were collected from various retail pharmacies through purposive sampling. The adequacy and accuracy of the information in each PI were evaluated with the help of a 25-item checklist prepared as per stipulations mentioned in statutory guidelines. Each required item of information was scored 1 if present and appropriate or 0 if absent or deemed incomplete or inaccurate. A total information adequacy score (IAS), with maximum value 25, was thereby calculated.Results:From the total 135 PIs analyzed, the median IAS was 17 (interquartile range 15–19). Deficiencies were observed under important headings. For example, “references” were mentioned in only 6.67% and “date of last updating” in only 19.26% of PIs. Other notable shortcomings were in “disposal” (not mentioned in 92.59%), “effects on ability to drive and use machines” (76.30%), “pharmaceutical incompatibilities” (66.67%), “shelf life” (62.96%), “excipients” (60.00%), and “overdose” (17.78%) information. Information on “generic name,” “composition,” and “indications” were however provided by all (100%) PIs.Conclusions:The information provided by PIs in India being inadequate, may not be able to serve as a reliable source of information.

Pharmaceutical Incompatibilities: Causes, Types and Major ways of Overcoming in Extemporaneous Medicinal forms

The objective of the work – is to study and analyze causes of incompatibilities, their types and ways of overcoming in extemporaneous prescriptions based on data from literary sources. In the work, the retrospective, logical, and analytical research methods have been used to analyze the data of special literature. Based on the data of modern scientific literature, causes of pharmaceutical incompatibilities, their types and major ways of overcoming in extemporaneous prescriptions have been studied and analyzed. The given information of the problem of pharmaceutical incompatibilities, in our opinion, will increase the professional knowledge of pharmacists about the physical phenomena and chemical interactions that may occur in dosage forms, types of pharmacological incompatibilities and will guide them in practical activities in preparation of extemporaneous medicines in different dosage forms.

Theoretical explanation for the pharmaceutical incompatibility through the cooperativity effect of the drug-drug intermolecular interactions in the phenobarbital∙∙∙paracetamol∙∙∙H2O complex.

In order to reveal the essence of the pharmaceutical incompatibility, the cooperativity effects of the drug-drug intermolecular π∙∙∙π and H∙∙∙O H-bonding interactions involving hydration were evaluated in the phenobarbital∙∙∙paracetamol∙∙∙H2O complex at the M06-2X/6-311++G** and MP2/6-311++G** levels. The thermodynamic cooperativity effects were also investigated by the statistical thermodynamic method. The results show that the π∙∙∙π stacking ternary complexes with the moderate anti-cooperativity effects are dominant in controling the aggregation process of phenobarbital, paracetamol, and H2O, as is confirmed by the atoms-in-molecules (AIM) and reduced density gradient (RDG) analyses. Therefore, it can be inferred that the anti-cooperativity effect plays an important role in forming the pharmaceutical incompatibility, and thus a deduction on the formation process of the pharmaceutical incompatibility between phenobarbital and paracetamol, with the hydration effect, is given. Several valuable models that relate the features of molecular surface electrostatic potentials or their statistical parameters, such as the surface areas, average values ([Formula: see text]), variances ([Formula: see text], [Formula: see text] and [Formula: see text]), and product of [Formula: see text] and electrostatic balance parameter (ν) ([Formula: see text]ν), to the values of the cooperativity effects were predicted. The formation of the pharmaceutical incompatibility is a thermodynamic cooperativity process driven by the enthalpy change. Graphical abstract Anti-cooperativity effect plays an important role in forming the pharmaceutical incompatibility.

Study of stability and drug-excipient compatibility of estradiol and pharmaceutical excipients

Estradiol (E2) is the main drug used in menopause therapy. This study aimed to evaluate the drug-excipient compatibility of binary mixtures (BMs) (1:1 BMs, w/w), initially by differential scanning calorimetry (DSC), and subsequently, by complementary techniques such as X-ray powder diffraction (XRPD) and high performance liquid chromatography (HPLC) if there was any evidence of interaction. The samples were stored under accelerated stability conditions (40 °C at 75 % relative humidity). The DSC curves of estradiol and the BMs with excipients (corn starch, lactose, xanthan gum, microcrystalline cellulose, magnesium stearate, dibasic calcium phosphate, and talc) were obtained. The results show that estradiol was compatible with all the selected excipients. XRPD and HPLC analysis were instrumental in interpreting the DSC results and excluding relevant pharmaceutical incompatibilities in all cases. Overall, the compatibility of the selected excipients with estradiol was successfully evaluated using a combination of thermal and spectroscopic methods, and the formulations developed using the compatible excipients were found to be stable.

Chick chorioallantoic membrane model for in ovo evaluation of timolol maleate–brimonidine tartrate ocular inserts

The main aspire of this study was to develop ocular drug delivery system for dual drug glaucoma therapy by timolol maleate–brimonidine tartrate and endeavor the possibility of biocompatibility studies by in ova studies. Matrix type, both hydrophilic and lipophilic polymers, and reservoir-type ocular inserts of timolol maleate were prepared using hydrophilic polymers like polyvinyl alcohol, hydroxyl propyl methyl cellulose K4M and lipophilic polymers like ethylcellulose and eudragit S100 and were optimized. Based on the optimized formulation, triple-layered ocular inserts (reservoir type) of dual drug were prepared by solvent casting technique with an objective of reducing the frequency of administration, obtaining controlled release and greater therapeutic efficacy, preservative free dosage form for the treatment of glaucoma. FTIR spectral studies revealed no pharmaceutical incompatibility and no drug polymer interactions. Maximum drug release (99.18 ± 1.7) was achieved when PVP and HPMC K4M in 1:1 ratio with PEG 400 (0.3 ml) drug reservoir layer was sandwiched between ethyl cellulose as rate control membrane up to 32 h in a controlled fashion. Drug release was by non-Fickian diffusion mechanism for single drug formulation. But in dual drug insert, timolol maleate best fit into zero order and for brimonidine tartrate to Higuchi model and diffusion of drugs from this by non-Fickian diffusion mechanism. In ovo studies suggested that the optimized formulation was found to be sterile, biocompatible and physicochemically stable and support us to claim that the developed formulation was biocompatible.

English

The current study was aimed to develop a stable sustained release drug delivery system for ibuprofen and a cytoprotective agent misoprostol in a combined dosage form. Non-aqueous emulsion solvent evaporation method was used to prepare ibuprofen microspheres. Ethylcellulose (EC) and Hydroxypropyl methylcellulose (HPMC) were used as the release retarding polymers in combination. Ibuprofen microspheres were prepared separately and then compressed into tablet dosage forms with misoprostol dispersions in HPMC. For surface topography of microspheres, Scanning Electron Microscope (SEM) was used. Fourier transformed infrared (FTIR) spectroscopy and X-ray diffractometry (XRD) were employed to evaluate pharmaceutical incompatibility and physical state of drug in formulation. The mechanism and pattern of drug release were determined by applying kinetic models. Tableted microspheres were also assessed for accelerated stability study for three months. SEM showed spherical shape microspheres. FTIR and XRD data for developed formulation indicated stability and compatibility of drugs with excipients. After 10 h, 86.97 and 89.33% of ibuprofen and misoprostol were released from micro particles while 75.43 and 77.65% from tableted microspheres, respectively. Non-aqueous emulsion solvent evaporation was found to be a suitable method to prepare stable sustained release tableted microspheres of ibuprofen and misoprostol in combination. &nbsp; Key words:&nbsp;Ibuprofen, misoprostol, hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), tableted microspheres, DDSolver&reg;.

PM101: intravenous amiodarone formulation changes can improve medication safety

Importance of the field: Intravenous amiodarone (A-IV) is used to manage ventricular and atrial arrhythmias. The current formulation uses polysorbate 80 and benzyl alcohol to maintain amiodarone in solution, and these co-solvents are linked with clinically-important adverse events and pharmaceutical incompatibilities. PM101 is a recently FDA-approved intravenous formulation of amiodarone that uses a cyclodextrin to solubilize amiodarone.Areas covered in this review: This review describes the clinical and pharmaceutical development of formulations of amiodarone for intravenous administration. The medical and pharmaceutical literature was searched for papers discussing A-IV, PM101 and their formulation components. Relevant literature was identified starting from 1948 to the present.What the reader will gain: The reader will learn about the important medical and pharmaceutical issues complicating A-IV administration, including an understanding of related hypotension and compatibility with commonly used infusion materials and how these issues may impact drug safety. PM101 has been developed to address several of these important issues.Take home message: PM101 is a new formulation of A-IV that is stable in commonly used infusion materials and avoids co-solvent related toxicities.

Compatibility study between ibuproxam and pharmaceutical excipients using differential scanning calorimetry, hot-stage microscopy and scanning electron microscopy

Differential scanning calorimetry (DSC) was used as a screening technique for assessing the compatibility of ibuproxam with some currently employed pharmaceutical excipients. The influence of processing effects (simple blending, cogrinding or kneading) on drug stability was also evaluated. On the basis of DSC results, ibuproxam was found to be compatible with corn starch, avicel and sodium carboxymethylcellulose. Some drug-excipient interaction was observed with polyethyleneglycol 4000, palmitic acid, stearic acid, Ca and Mg stearate. Actual solid-phase interactions of the drug with polyvinylpolypyrrolidone and polyvinylpirrolidone K30 were induced by mechanical treatments. Hot-stage microscopy (HSM) and scanning electron microscopy (SEM) were of help in interpreting the DSC results and excluding in all cases relevant pharmaceutical incompatibilities.

Effect of gentamicin on heparin activity

The importance of the effect of gentamicin on heparin activity was investigated. Heparin activity was assessed using the activated partial thromboplastin time (APTT), thrombin clotting time (TCT), and Factor X heparin assay. Drug concentrations used were 0.1, 0.2, 0.3, and 0.4 units/ml heparin with 40, 80, and 400 microgram/ml gentamicin, in vitro in human plasma. The drugs were precipitated at concentrations of 10, 20, 30, and 40 units/ml heparin with 4 and 40 mg/ml gentamicin. After centrifuging, the supernate was diluted to 0.1-0.4 units/ml heparin for assay. There was no change in heparin activity in the presence of gentamicin (in the unprecipitated solutions) as measured by the TCT, Factor X assay, and the APTT; however, APTT was prolonged by gentamicin. In the precipitated samples, heparin activity was lost in the precipitate. No significant clinical interaction that would affect the therapeutic efficacy of heparin was demonstrated except for a pharmaceutical incompatibility between gentamicin and heparin. The APTT, performed with ellagic acid as an activator, is prolonged by gentamicin.

Incompatibility of Fulaid Fine Granules

Pharmaceutical incompatibility of Fulaid Fine Granules (TF) with other 67 agents was investigated under various conditions. TF was found to be a stable agent.

Predicting Pharmaceutical Incompatibilities of Parenteral Medications

Predicting Pharmaceutical Incompatibilities of Parenteral Medications

Predicting pharmaceutical incompatibilities of parenteral medications

Predicting pharmaceutical incompatibilities of parenteral medications

Incompatibility in Prescriptions and How to Avoid It, to Which is Added a Dictionary of Incompatibilities.

This is a collection of various incompatibilities which have appeared from time to time in the<i>Prescriber</i>, of which the author is editor. That it met with popular demand, particularly in Great Britain, is evidenced by the fact that, since 1915, it has gone through three editions. Part I is devoted to general principles of incompatibility, including chemical incompatibility, physical or pharmaceutical incompatibility, and therapeutic incompatibility. Part II is a small dictionary of incompatibilities containing an alphabetical summary of drugs with their doses and solubilities. The booklet should find a ready place on the desk of the busy prescribing physician.