Impact of solid state properties of sodium naproxen hydrates on their technological performance

Sodium naproxen, a member of the class of non-steroidal anti-inflammatory drugs (NSAIDs), exists in one anhydrous form and four hydrated ones: one monohydrate, two dihydrate and one tetrahydrate. Sodium naproxen (SN) forms can be summarised as follows:\ud • the anhydrous sodium naproxen (ASN) is the commercialised form;\ud • the monohydrated sodium naproxen (MSN), is obtained by dehydration of the dihydrated sodium naproxen (DSN), according to Kim and Rousseau (2004);\ud • the dihydrated sodium naproxen (DSN) is obtained by exposing the ASN to 55% RH according to Di Martino et al. (2001);\ud • the dihydrated sodium naproxen (CSN) is obtained by crystallizing sodium naproxen from water, according to Di Martino et al. (2001) and Kim and Rousseau (2004);\ud • the tetrahydrated form (TSN) is obtained by exposing the ASN at 75% RH according to Di Martino et al. (2007).\ud The hydration state of SN may strongly influence its physico-chemical and technological properties and consequently its bioavailability. Water exposure during\ud storage or pharmaceutical processing can cause changes in the crystal lattice of the starting material. Therefore, a profound understanding and characterisation of SN solid\ud state and phase transitions throughout storage or processing are important in predicting and defining its technological performance.\ud In fact, it was observed that following wet granulation process by high-shear mixergranulator, the drug hydrated to the tetrahydrated form. Performing two different drying\ud procedures, granules of different water content and crystallographic characteristics were obtained. This means that differences in drying procedures could lead to products of different crystallographic properties. The behaviour under compression revealed that one of the batches offered the best tabletability and compressibility. These results make it possible to state that differences in the crystallographic properties and water content of\ud sodium naproxen are such that different hydration/drying processes can alter the drug crystal form and thus the tabletability of the resulting granules.\ud Next, the water uptake of ASN during storage was evaluated. A correlation between water uptake by ASN at two different relative humidities and modifications in tableting and\ud densification behaviour under hydration exists. Models for the hydration kinetics of ASN at 55% and 86%, corresponding to the formation of the dihydrated and tetrahydrated forms\ud respectively, were evaluated assuming Eyring’s dependence on temperature. Tabletability, compressibility, compactibility and densification behaviour were determined using an instrumented single punch tablet machine.\ud Kinetic data is consistent with a model where water molecules enter the crystal preferentially along hydrophilic tunnels existing in the crystal structure and corresponding to the propionate side chain. Water inclusion perturbs the crystallographic structure, causing slight structural changes according to the amount and associated to an increase in entropy. The interposition of water molecules between SN molecules weakens intermolecular bonds, and these sites can behave like sliding planes under compression.\ud Such structural changes may explain the improved compression behaviour and modified densification propensity mechanism. Kinetic data describing the water hydration\ud mechanism of ASN explains in an original way the improved tableting and densification properties under hydration.\ud Because different hydration/dehydration processes can alter the drug crystal form, the isothermal dehydration of some of SN hydrates was observed by thermogravimetry at several temperatures. The rate of water removal from the crystal was used to determine the mechanism of dehydration in the solid state, by fitting results with selected expressions\ud corresponding to the most common solid-state processes. The water loss was then evaluated according to Eyring’s equation, and both changes in activation enthalpy ( ÄH*)\ud and activation entropy ( ÄS*) were estimated from rate constant values. Experiments made it possible to distinguish different dehydration mechanisms for these hydrate forms, and in particular, to discern the dehydration behaviour of CSN and DSN dihydrate forms. These\ud results add new evidence supporting the X-ray powder diffraction study and showing different patterns for these two forms. X-ray powder diffractometry evaluation of the phase transitions occurring during dehydration of these two dihydrate forms showed that they vary according to dehydration temperature.\ud To finalize our study, the technological and mechanical properties of several solid forms of SN were investigated. Particular attention has been made in order to reduce\ud differences, among the samples, in crystal habit, particle size and distribution, amount of absorbed water, so that only the hydration degree and the crystalline structure might affect the technological behaviour of powders. Thus, the compression behaviours were determined by using an instrumented single punch tablet machine and evaluated through the tabletability, compressibility and compactibility analysis. The results showed that the\ud compression ability was influenced by the hydration degree and the crystalline form. In general, the tabletability was mainly due to the ability of particles to close up by\ud establishing numerous bonds.\u

STATISTIC ESTIMATION OF BREAKING TABLETS OF ENALAPRIL 20 MG

Objective: The aim of this study was to evaluate the accuracy of breaking into half and quarter-tablets Enalapril 20 mg sold in the Albanian market, in dosages suitable for use in children.Methods: 100 whole tablets of Enalapril 20 mg were chosen at random from each of three different manufacturers based on scoring characteristic: scored on one side, scored on both sides and not scored. Whole tablets from each of the three product types were weighed and the mean weight calculated. The pills were then split in half and quarter by using a pill-splitter. The resulting half-tablets and quarter-tablets were weighed and the mean weights were calculated.Results: All the whole tablets were found to conform to the set criteria. Only halves from those tablets scored on both sides passed the weight uniformity test, with no individual half outside the 85-115 % range. Quarter-tablets failed the weight uniformity test. A higher relative standard deviation was observed for half and quarter-tablets of the not-scored tablet.Conclusion: The study shows that deviations in weight were observed in half tablets and quarter tablets of Enalapril 20 mg. These deviations were related to the presence or not of the score line. Such inadequate breaking of the tablets may result in dose variability and complicate therapeutic outcome.Keywords: Enalapril, Breaking tablets, Pediatric formulations, Score lin

A COMPARATIVE QUALITY CONTROL STUDY OF CETIRIZINE HYDROCHLORIDE 10MG TABLETS ON THE ALBANIAN PHARMACEUTICAL MARKET

Objective: The aim of this study was to carry out a quality control test on a range of different production of cetirizine hydrochloride 10mg tablets and to compare the generic productions with the reference one in order to evaluate if there are any outstanding differences in terms of quality and price.Methods: Various pharmacopeias tests were carried out: weight variation test, disintegration test, dissolution test, as well as other tests such as: setting the diameter, thickness, tensile strength, friability and hardness test. The pharmaceutical equivalents were compared to the reference product in terms of similar dissolution factor (f2) of dissolution profiles and the evaluation of dissolution efficiency (DE). Tablet dissolution was carried out in a multi bath (n=6) dissolution test system (Varian Dissolution Apparatus 2) (50rpm, 37.0±0.5 ºC, bi distillated water 900 ml, pH 7.0). An UV-Vis spectrophotometer (Cary 100, Varian) was used to determine cetirizine concentration at wavelength 230.1 nm. Varian Hardness VK200, Guoming CS-2 friability apparatus and Guoming BJ-2 disintegration apparatus are used for the specific tests.Results: The study showed that all the products met with the standards of pharmacopoeia and that dissolution profiles were significantly the same but, however, there is also a remarkable difference in price.Conclusion: All the productions met the requirements and are within the limits of pharmacopoeia for the presented tests. Cetirizine reference product still sells well on the open pharmaceutical market even though it costs more and regardless of the fact that other generics have practically the same qualities.Â

Some H2 Antihistaminics And Ppi-S Products Authorized In Albania And Their Availability For Pediatric Groups

The objective of this study was to evaluate the number of medicines and active ingredients for pediatric population that are authorized and marketed in Albania. For this purpose were selected two group’s medicines: H2 antihistaminics and Proton Pump Inhibitors. The availability of pediatric medicines and active ingredients was studied with the help of the database of the Albanian National Agency for Medicine and Medical Devices and SmPCs. Selected active ingredients were categorized based on their route of administration, type of pharmaceutical form, dosage, therapeutic indication, dose capability and suitability of the pharmaceutical form for use in children. From evaluation of SmPCs of selected products for the authorized age - group were found that 58 products are also authorized for use in children. Two of the active ingredients are authorized only for use in adults. The analyze of aspect if the recommended dose prescribed based on the classification of pediatric age stated give these data’s: 35 products are authorized for use children and adolescents from 3–18 years and 23 products are authorized for use in children more than 1 year old. This study shows a lack of availability of pediatric medicines for selected products and shows that pediatric medicines may not be age-appropriate; even they are authorized for such use. It was shown that few medicinal products are specifically studied in children. Therefore, are needed more efforts to increase the number of drugs authorized for the pediatric groups. Even more, it is required by pharmaceutical companies to supply data on the effects of new drugs in children

A COMPARATIVE STUDY ON THE QUALITY OF DIFFERENT OLMESARTAN TABLETS AVAILABLE IN THE ALBANIAN MARKET

ABSTRACTObjective: Olmesartan (OLM) is the latest molecule of registered and marketed in Albania for the treatment of arterial hypertension. This study aimsto carry out a quality control (QC) test on all the alternatives available in the Albanian market and evaluate if there are any outstanding differencesterms of quality as it is in terms of price.Methods: There were carried out various QC pharmacopeias tests on a range of different productions of OLM 20 mg tablets. There have been carriedout weight variation test, setting the diameter, thickness, friability, hardness, disintegration, and dissolution test. The pharmaceutical equivalents werecompared to the reference product in terms of similar dissolution factor (f) of dissolution profiles and the dissolution efficiency. The dissolution test wascarried out using Varian dissolution apparatus 2 (50 rpm, 37±0.5°C); Varian Prostar high-performance liquid chromatography was used to determine theOLM concentration at wavelength 250 nm; Varian hardness VK 200, Guoming BJ-2 disintegration apparatus were used for the respective tests.2Results: The study showed that although there is a consistent difference in market price, their quality is comparable. The dissolution profiles werevery similar. All formulations met the standards of the United States Pharmacopoeia.Conclusion: All tablets were within the pharmacopoeia limits. The present study confirmed that the difference in price not always represents adifference in terms of quality.Keywords: Olmesartan medoxomil, Quality control, Pharmacopoeia standards

A COMPARATIVE STUDY ON THE EFFICACY OF THREE GALENIC PREPARATIONS FOR TOPICAL USE

Background: Atopic dermatitis, eczema, psoriasis are an important challenge for dermatology doctors. In order to have the best result in shorter time of treatment, it is necessary a collaboration with clinical pharmacists to have the right product, for the right type of skin, in the right amount according to the affected surface. It is very important to decide first which NSAID to use as topical therapy, second the type of formulation to use having at disposal Galenic preparations such as lotion, cream and unguent Objective: To study the efficacy and compliance of patients on three Galenic preparations. Method: A randomized, open group controlled trial. 198 patients were included in this trial to be treated either with lotion of 0.1%, cream of 0.1% or unguent 0.1% mometasone furoate (MF). The data were analyzed with chi-square test. Results: About 118 (59.6%) of patients were males and 80 (40.4%) were females. The male/female ratio was 1:0.67. After 28 days of treatment quite all patients were improved or had no signs of illness (lotion 97.6% improved, cream 80% absence of signs, unguent 63.0 % improved). The results after statistical analysis shows that there are much more possibility to become absent from signs using cream, rather than lotion or unguent [cream vs lotion 157 folds (P= 0.002) while unguent vs lotion 25 folds (P<0.001)]. There were not noticed any treatment-related irritation from all three formulations. Conclusion: All three formulations can improve the health status of patients with eczema, dermatitis or psoriasis. However cream gives faster and better clinical improvements compared to unguent or lotion. All three galenic preparations were well tolerated

SPECTRUM OF INFECTIOUS DISEASES AND ANTIBIOTIC USAGE IN A PAEDIATRIC OUTPATIENT DEPARTMENT

The main objective of this study is to analyze the spectrum of infectious diseases in paediatric population and to study the antibiotic usage and selection of the dosage forms in children taking treatment in the outpatient department of the paediatric hospital in Tetovo. A retrospective study was undertaken during 01 January – 30 June of 2012. Drug data and patient characteristic data were computed using Ms. Excel 2007. Among the total number of 3778 patients analyzed during the period of six months, 1463 (38.7 %) of them were prescribed antibiotics, male patients were 829 (56.7%) and female patients were 634 (43.3 %). The majority of patients given antibiotics were aged >1 - ≤ 3 years (49.1 %). Incidence of infections was found to be 89.3% (1306 patients), of which upper respiratory tract infections (69.7%) were common among 1020 patients followed by lower respiratory tract infections in 234 (16.0%) cases. Cephalosporins were the commonest antibiotics prescribed (43.6%), among which cefaclor was the leading antibiotic prescribed in 283 (19.3 %) the total patients. Benzathine phenoxymethylpenicillin was the most common antibiotic prescribed in upper respiratory tract infections (23.8%) followed by cefaclor (19.7%). Syrups were the common dosage forms prescribed for all patients in the paediatric age group followed by capsules

The Influence of Division of Amlodipine Tablets on Their Efficacy and Stability

Tablet division is a widespread phenomenon nowadays in Albania, because of different factors such as the absence of small dosages in the pharmaceutical market, financial reasons etc. The purpose of this study is to identify the positive and negative aspects of tablets division by patients. It aims to show experimentally if the division affects or not, in a significant way the percentage of the active substance. It was selected Amlodipine as a drug for analysis, because of two reasons. First it is used in chronic therapy and second it is part of the List of Reimbursement of Medicines in the Republic of Albania.It was used besylate amlodipine as RS, three different productions of Amlodipine tablets bought directly in a community pharmacy, methanol HPLC grade and ammonium acetate. It was selected the method based on the HPLC analysis of the solutions obtained by dissolution of amlodipine in methanol as described in the European Pharmacopoeia 2011. This was an ongoing analysis for four weeks. The divided tablets have been kept in similar conditions as a patient can do.The organoleptic control after division showed no changes for all three productions. Only halves of sample A fulfill the pharmacopoeia criteria for RD ± 7.5%. From the results obtained, it was noted that there was a decrease in the percentage of the active substance, on halves taken randomly for analysis. The concentration of the active substance in sample A at the end of the analysis resulted to be 83.6%, in sample B 84.37% and sample C 83.75%. The level of impurities remain ≤ 2% conform limits in Eur. Ph. Based on these results, it is concluded that tablet division is a process that significantly affects the percentage of the tablet\u27s active substance. Reducing the concentration of the active substance implies that the patient does not receive the required dose for treatment and the success of therapy is in doubt. The division of amlodipine tablets is economically convenient, but is a practice that should be avoided and not advised by the healthcare providers

MANAGEMENT OF HYPERCOAGULABLE STATE DURING PREGNANCY. PROPHYLACTIC USAGE OF LOW MOLECULAR WEIGHT HEPARIN (LMWH)

The main objective of this study is to analyze the prophylactic usage of low molecular weight heparin, in women during the period of pregnancy. A retrospective study was undertaken during 01 January – 31 December of 2013, in the Department of Gynecology and Obstetrics, at Clinical Hospital in Tetovo. Data were collected for the following: patient demographics, week and month of pregnancy, number of pregnancies for each patient, duration of hospital stay, clinical and laboratory investigations, diagnosis, drug details; which include the name of the drug, dosage form, dose frequency, total cost of the drug, the amount of each given ampoule application and the cost for the entire period of hospitalization. Among of 643 women whom were prescribed LMWH, 144 of them were found hypercoagulable. The majority of patients given LMWH were aged 25-30 years (56.25 %). For the biggest number of patients, this was their first pregnancy (70.83%). Earliest phase of using LMWH was the second month of pregnancy, respectively sixth week. Patients during the ninth month, apear to be more affected by hypercoagulable statete. 56 (38.89 %) women were in the ninth month of pregnany. Fraxiparine (nadroparin calcium) 3800 IU anti-Factor XA in 0.4 ml was the most prescribed anticoagulant, 64 (44.44 %) patients received this therapy. From the total number of 144 patients, only 4 of them received LMWH twice a day

A COMPARATIVE STUDY ON THE EFFICACY OF THREE GALENIC PREPARATIONS FOR TOPICAL USE

Background: Atopic dermatitis, eczema, psoriasis are an important challenge for dermatology doctors. In order to have the best result in shorter time of treatment, it is necessary a collaboration with clinical pharmacists to have the right product, for the right type of skin, in the right amount according to the affected surface. It is very important to decide first which NSAID to use as topical therapy, second the type of formulation to use having at disposal Galenic preparations such as lotion, cream and unguent Objective: To study the efficacy and compliance of patients on three Galenic preparations. Method: A randomized, open group controlled trial. 198 patients were included in this trial to be treated either with lotion of 0.1%, cream of 0.1% or unguent 0.1% mometasone furoate (MF). The data were analyzed with chi-square test. Results: About 118 (59.6%) of patients were males and 80 (40.4%) were females. The male/female ratio was 1:0.67. After 28 days of treatment quite all patients were improved or had no signs of illness (lotion 97.6% improved, cream 80% absence of signs, unguent 63.0 % improved). The results after statistical analysis shows that there are much more possibility to become absent from signs using cream, rather than lotion or unguent [cream vs lotion 157 folds (P= 0.002) while unguent vs lotion 25 folds (P<0.001)]. There were not noticed any treatment-related irritation from all three formulations. Conclusion: All three formulations can improve the health status of patients with eczema, dermatitis or psoriasis. However cream gives faster and better clinical improvements compared to unguent or lotion. All three galenic preparations were well tolerated