ABSTRACT
In this paper the theoretical background of dissolution determining the oral administration, the physicochemical and physiological factors influencing the rate of dissolution, the relation between solubility and dissolution, the most important pharmacopoeial and miniaturized dissolution measurements and finally the dissolution in biorelevant media are reviewed.
Subject(s)
Administration, Oral , Dosage Forms , Laboratories/standards , Solubility , Equipment Design , HumansABSTRACT
The present article summarizes the features of human skin as absorption site and describes a new model for skin penetration prediction. The parallel artificial membrane permeability assay (PAMPA), a high throughput method that serves as the basis of the model is also discussed in details demonstrating its features and published applications. The paper focuses on the steps of model development and on the comparisons to human skin datasets. The one dataset by J. Hadgraft and R. Guy, containing over 100 compounds, was divided into groups corresponding to similar experimental conditions (e.g. skin type and temperature) and drug-likeness. Skin PAMPA results correlate supremely with Franz cell results measured on full thickness skin at 37 degrees C (R2=0.89). The other dataset reported by Lee et al. contains experiments with 40 compounds (27 of it is drug-like) on dermatomed skin at 32 degrees C. The Skin PAMPA permeability results show a high correlation (R2=0.84;) with it if similar experimental conditions have been applied. Intra- and inter-laboratory reproducibility has been also proved and homogeneity has been examined. The developed Skin PAMPA model is able to predict human skin permeability reasonably well, and because of its good reproducibility and 96-well based format it can be a cost effective alternative to Franz cell studies for early skin penetration prediction.
Subject(s)
Cell Membrane Permeability , Models, Biological , Skin, Artificial , Skin/metabolism , Absorption , Humans , In Vitro Techniques , Membranes, Artificial , Reproducibility of ResultsABSTRACT
In this paper the pH-equilibrium solubility profiles of ionizable drugs are presented. The aim of the present work was to study the validity of the Henderson-Hasselbalch (HH) relationship in the case of structurally diverse weak bases. In the case of monoprotic bases, namely papaverine, promethazine and propafenone the experimental equilibrium solubility data precisely follow the theoretical HH curve until the limit of salt solubility. The common ion effect on salt solubility was found to be significant at low pHs. Deviation from the HH equation in the case of dibasic quetiapine hydrogen fumarate can be easily interpreted with the formation of different salt compositions. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. It is critical that the pKa value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs.
Subject(s)
Hydrogen-Ion Concentration , Solubility , Dibenzothiazepines/chemistry , Ions , Laboratories/standards , Papaverine/chemistry , Promethazine/chemistry , Propafenone/chemistry , Quetiapine Fumarate , Reproducibility of Results , Sodium Chloride/chemistry , WaterABSTRACT
In the present part of our series of papers a study on theophilline containing suppositories prepared in pharmacies is described. From the possible methods for assay of theophilline two nonaqueous titrations are compared. In first, theophilline is measured as a very weak base in a mixture of glacial acetic acid and acetic anhydride with perchloric acid using Sudan-III indicator, in second, the compound is measured as medium strong acid in dimethylformamide solvent with sodium-hydroxide titrant using phenolphtalein indicator. These methods were validated and the first was found more appropriate for regulatory control. We investigated suppositories prepared in our laboratory and in different pharmacies. The study revealed the poor quality of the preparations due to the difficulties in the technology and the importance of the applied vehicle. A guideline for the good preparation practice and an alternative technology are proposed.
Subject(s)
Pharmaceutical Preparations/standards , Pharmacies/standards , Suppositories/standards , Theophylline/standards , Hungary , Quality Control , Theophylline/analysisABSTRACT
Quality controll has fundamental importance in drug safety. During the last 15 years the regulatory changes resulted many problems in the quality controll of pharmaceutical preparations manufactured in pharmacys. The issue of Formulae Normales (FoNo VII.) and the 8th Hungarian Pharmacopoeia raises further questions. Our intentions to show the results have been achived in the area of elaborating new analytical prescriptions (identification and assay) which are crucial due to the obsolescence of previously used prescriptions.
Subject(s)
Pharmaceutical Preparations/standards , Pharmacies/standards , Hungary , Pharmacopoeias as Topic , Quality Control , SafetyABSTRACT
The paper represents the last (6th) part of a series about agents acting on the central nervous system. This time the minor analgesics and the non-steroidal antiinflammatory agents are surveyed. As previously, the material is divided into chapters of history, preparation; structure-properties-activity; therapeutical use; analysis.
Subject(s)
Analgesics/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Acetaminophen/chemistry , Aspirin/chemistry , Chemistry, Pharmaceutical/methods , Diclofenac/chemistry , Molecular Structure , Spectrophotometry, InfraredABSTRACT
In our previous paper identification methods using chemical reactions and TLC are described for the active ingredients of pharmaceutical preparations in Formula Normales (FoNo VII.). Present paper introduces the development and validation of analytical methods suitable for quantitative determination of paracetamol containing dosage forms in FoNo VII. Titrimetric methods, UV spectroscopy and HPLC are used for assay of paracetamol and accompanying components (e.g. codeine, papaverine, caffeine and acetylsalicylic acid) in these preparations.
Subject(s)
Acetaminophen/standards , Chemistry, Pharmaceutical/standards , Aspirin/standards , Caffeine/standards , Ethylmorphine/standards , Hungary , Quality ControlABSTRACT
The paper represents the 4th part of a series about agents acting on the central nervous system. This time the antidepressants are surveyed. As previously, the material is divided into chapters of hystory, preparation; structure-properties-activity; therapeutical use; analysis.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/therapeutic use , Antidepressive Agents/classification , Humans , Molecular Structure , Structure-Activity RelationshipABSTRACT
The paper represents the 5th part of a series about agents acting on the central nervous system. This time the major analgesics are surveyed. As previously, the material is divided into chapters of hystory-preparation; structure-properties-activity; therapeutical use; analysis.
Subject(s)
Analgesics, Opioid/chemistry , Amino Acid Sequence , Analgesics/chemistry , Analgesics/isolation & purification , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/classification , Chemistry, Pharmaceutical , Molecular Sequence Data , Molecular Structure , beta-Endorphin/chemistryABSTRACT
The paper represents the 3rd part of a series about agents acting on the central nervous system. This time the neuroleptics are surveyed. As previously, the material is divided into chapters of history, preparation; structure-properties-activity; therapeutical use; analysis.
Subject(s)
Antipsychotic Agents/chemistry , Central Nervous System Depressants/chemistry , Models, Molecular , Structure-Activity RelationshipABSTRACT
The paper represents the 2nd part of a series about agents acting on the central nervous system. As previously, the material is divided into chapters of hystory, preparation; structure-properties-activity; therapeutical use; analysis.
Subject(s)
Anti-Anxiety Agents/chemistry , Central Nervous System Agents/chemistry , Hypnotics and Sedatives/chemistry , Anti-Anxiety Agents/history , Central Nervous System Agents/history , Central Nervous System Agents/therapeutic use , History, 20th Century , Humans , Hypnotics and Sedatives/historyABSTRACT
The paper represents the first part of a planned series of reviews about pharmaceutical chemistry of drugs acting on the central nervous system. The authorial aim and editorial concepts are the same were followed in a former series of papers about pharmaceutical chemistry of agents effecting the heart, blood circulation and vegetative nervous system. Consequently, general anaesthetics are discussed in the present paper through the chapters "history, preparation; structure-properties-activity; application; analysis".
Subject(s)
Anesthetics, General/chemistry , Chemistry, Pharmaceutical/methods , Anesthetics, General/pharmacology , Blood Circulation/drug effects , Heart/drug effects , Humans , Nervous System/drug effectsABSTRACT
The European Pharmacopoeia introduced a new alkalimetric method for assay of alkaloid (and other N-base) salts. The principle of method is: after preliminary addition of small amount of hydrochloric acid, titration is carried out with 0.1 N NaOH in alcohol/water mixture with potentiometric end-point detection. The applicability and reproducibility of this method have been examined at 11 substances. The results of alkalimetric method were compared to those obtained by nonaqueous titration (Ph. Hg. VII.). The method of Ph. Eur. is well reproducible (SD < +/- 0.50), however it could not be applied in case of some compounds (4 cases out of 11). Authors revealed that for the titration carried out according to the present prescription of Ph. Eur. 4., minimum pKa 7 should be the basicity of the alkaloids. They suggest to perform the titration in 70% alcohol and without preliminary addition of HCl for weaker bases.
Subject(s)
Ethanol , Hydrogen-Ion Concentration , Pharmacopoeias as Topic , Water , Europe , Potentiometry/methods , Reproducibility of ResultsABSTRACT
The excitatory neurotransmitter, Glu, plays a crucial role in many sensory and motor functions as well as in brain development, learning and memory and it is also involved in the pathogenesis of a number of neurological disorders, including epilepsy, Alzheimer's and Parkinson's diseases. Therefore, the study of Glu receptors (GluRs) is of therapeutical importance. We showed here by fluorescence monitoring of transmembrane Ca2+ ion fluxes in response to (S)-alpha-amino-3-hidroxi-5-metil-4-izoxazol propionic acid ((S)-AMPA) on the time scale of 0.00004-10 s that Ca2+ ion influx proceeds through faster and slower desensitizing receptors. Pharmacological isolation of the slower and faster desensitizing AMPA receptor was possible by fluorescence monitoring of Ca2+ ion translocation in response to (S)-AMPA in the presence and absence of various 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxilic acid derivatives (Qxs): the acetic acid Q1 inhibits the slower desensitizing receptor response specifically, while the acetyl-piperidine Q5 is a more potent inhibitor of the faster desensitizing receptor response. In addition, spontaneous interictal activity, as induced by high [K+] conditions in hippocampal slices, was reduced significantly by Q5, suggesting a possible anticonvulsant property of Q5. Substitutions of Qxs into the GluR2 S1S2 binding core were consistent with their effect by causing variable degree of S1S2 bridging interaction as one of the main determinants of AMPA receptor agonist activity. The exploitation of differences between similar receptors will be important in the development and use of drugs with high pharmacological specificity.
