Paracetamol Dissolution Research Articles

Modeling of Nucleation, Growth, and Dissolution of Paracetamol in Ethanol Solution for Unseeded Batch Cooling Crystallization with Temperature-Cycling Strategy

Controlling crystal size distributions is critical to ensure the quality of products and operational efficiency for downstream processing. In batch cooling crystallization, temperature cycling strategies are often employed to control the crystal size distribution and minimize fines. Optimizing the complex operation of this strategy, where crystallization and dissolution occur in a single batch run, remains a challenge. For this problem, we develop a model of the process by a population balance considering nucleation, growth, and dissolution of crystals. In a case study of paracetamol in ethanol, the parameters in the population balance model were estimated from multiple experimental runs. The developed model was validated against additional experimental data sets, where the concentration and crystal size distributions of the final crystal products were predicted successfully. R2 values are greater than 0.96 in all cases.

HPLC and chemometrics-assisted spectroscopic methods used for determination of dissolution of paracetamol and orphenadrine citrate in a combination tablet

HPLC and chemometrics-assisted spectroscopic methods used for determination of dissolution of paracetamol and orphenadrine citrate in a combination tablet

Investigation of dissolution rate kinetics of bulk pharmaceutical feed streams within a stirred tank vessel and a twin screw extruder

The introduction of continuous manufacturing of pharmaceuticals has highlighted the challenging area of continuous dissolution of solids for work ups to flow chemistry systems. In this study, the use of a 16 mm twin screw extruder (TSE) as a platform technology for solid feeds is investigated using four solid pharmaceutical ingredients (PI) in a mixture of water and IPA. In order for comparison, the same experiments were also carried out in a batch traditional stirred tank vessel (STV). The objectives of this work are to gain further scientific understanding on dissolution kinetics and to compare kinetics in both a batch and continuous system. The concentration of each PI during dissolution is monitored using an in-line UV-ATR probe, allowing the extraction of dissolution kinetics. Faster dissolution rates are achieved in the TSE than in the STV due to higher power dissipation generated by the aggressive shear mixing and thermal energy within the TSE. Complete dissolution of paracetamol is obtained within the residence time of the TSE; complete dissolution of benzoic acid and acetylsalicylic acid are achieved at higher barrel temperatures; however full dissolution of nicotinic acid is not achievable in the TSE under the experimental conditions.

Uticaj formulacije tableta sa trenutnim oslobađanjem na profil brzine rastvaranja paracetamola

Introduction: Paracetamol is analgesic and antipyretic, which is usually in the form of an immediate release tablet formulations. Therapeutic effects in terms of the speed and intensity of the analgesic effect is dependent on speed of liberation from formulation. Aim: The aim of this work was to determine and compare dissolution profiles of 4 paracetamol immediate release tablet formulations and to determine influence of excipients on kinetic of paracetamol dissolution. Materials and Methods: Dissolution profiles of paracetamol tablets were determined using method with paddles and phosphate buffer pH 6.8 as a medium. Release of paracetamol was followed 60 minutes (using 6 time points). Concentration of paracetamol was measured using UV/Vis spectrophotometric method (243 nm). Dissolution profiles were compared using model-independent method (difference factor and similarity factor), statistic method (ANOVA-based method and pair Student's T-test, p<0.05) and model dependent methods (to determinate the release kinetics of paracetamol). Results: All formulations in the first 45 minutes liberated more than 85 % of the labled content. Formulation D, which contained superdesintegrator, released 90% of the content in the first 5 minutes. Though based on values of difference and similarity factors formulations are, not significantly different, ANOVA-based method showed that formulation A and B, B and C, as well as formulation B and D do statistically differ in all 6 time points, meaning they have parallel profiles. The release of paracetamol from formulations A and D is best described by the first order kinetic model, while the release of formulations B and C by the logistic model. Conclusions: The release kinetic of paracetamol is mostly influenced by the type of superdisintegrants and lubricants. Formulation with superdisintegrant technology OptiZorb® demonstrated fastes release rate and thus it is expected to produce the fastest pharmacodynamic effect. .

Core-Shell Medicated Nanoparticles Prepared Using Coaxial Electrospray for Fast Dissolution of Paracetamol

Background The dissolution of insoluble drugs is one of the most intractable challenges in pharmaceutics, particularly for those used to rapidly bring down a fever or stop pain. Advanced technologies are frequently introduced into this field for developing nano drug delivery systems (DDS) for this purpose. Methods Coaxial electrospray is a popular advanced process for creating core-shell micro-/nano-structures. Here, a core-shell nano DDS was fabricated and characterised in detail for enhancing the fast dissolution of paracetamol. A surfactant solution (consisting of 0.5% w/v Triton X-100% and 10% w/v polyvinylpyrrolidone (PVP) K10 in ethanol) and a drug solution (composed of 5% w/v paracetamol and 10% w/v PVP K10 in ethanol) were exploited. Results Under the selected conditions (an applied voltage of 20 kV, a collecting distance of 15 cm, and a shell-to-core fluid flow rate ratio of 0.5/1.5 mL/h), uniform core-shell nanoparticles were stably and continuously fabricated. Owing to the secondary interactions between PVP and paracetamol, the particles were amorphous composites, as verified by the XRD patterns and attenuated total reflectance–FTIR spectra. The nanoparticles could release the loaded cargoes within one minute after they were placed into the dissolution media. Conclusion Core-shell medicated nanoparticles prepared using coaxial electrospray can be an alternative approach for improving the dissolution rate of insoluble drugs. Acknowledgements Supported by the National Natural Science Foundation of China (No. 51373101).

Modeling and analysis of dissolution of paracetamol/Eudragit® formulations

In this work, amorphous paracetamol/Eudragit® formulations for four Eudragit® (polymeric excipients) were prepared by spray drying technique. The simultaneous dissolution kinetics of paracetamol and Eudragit® from these formulations were measured as function of pH in vitro using a rotating disk system (USP II). Paracetamol dissolution mechanisms were analyzed by comparing the dissolution rates of paracetamol and excipient. It was found that a controlled paracetamol dissolution was achieved from Eudragit® L 100-55 and Eudragit® E PO formulations at pH 5.0, 6.5, and 7.2. Furthermore, a controlled paracetamol dissolution was also achieved from Eudragit® L 100 formulations at pH 6.51 and 7.27 as well as from Eudragit® S 100 formulations at pH 7.27. Paracetamol dissolution rates were controlled by both paracetamol and excipient from Eudragit® L 100 and S 100 formulations at other pH values. Moreover, a chemical-potential-gradient model combined with PC-SAFT was used to model the dissolution kinetics of PARA from these formulations in good accordance with the experimental data.

ENHANCEMENT OF THE IMMEDIATE RELEASE OF PARACETAMOL FROM ALGINATE BEADS

Objective: Alginate beads are not soluble in the acid leading to small portion released in the stomach. This may not be favourable for drugs administered for fast action like paracetamol. So, this study was aimed to increase the immediate release of paracetamol from alginate beads, i.e. the release in the acidic pH.Methods: The beads were prepared by dropwise paracetamol/alginate suspension in divalent cation solution. Two attempts were used to increase the dissolution of paracetamol in the acidic pH. First attempt was by only changing preparation variables: needle size, alginate viscosity and drug loading using 23 full factorial design. The second approach was by adding excipients like carbopol, tween and polyethylene glycol. The beads were characterized for their size, encapsulation efficiency and release profile.Results: First approach, changing preparation variables without excipient adding, helped to increase the drug release in the acid but to a maximum of 26% using a smaller needle, lower drug loading and higher alginate viscosity. However, optimising the formulation with suitable excipients increased the drug release in the acid to 77.3%. The optimised formulation included carbopol 940 (pH sensitive polymer) and tween 80 (facilitates water entry) in the beads, with using barium chloride instead of calcium chloride together with PEG 400 in the complexing solution.Conclusion: To achieve immediate release of paracetamol from alginate beads in the acidic pH, excipients need to be added. Rational selection of excipients is critical to achieve the desired drug release.

In vitro-In vivo Drug Interaction Study of Paracetamol and Propranolol Hydrochloride

Introduction: Propranolol Hydrochloride is a non-cardio selective beta-adrenergic antagonist, used in the treatment or prevention of many disorders, including acute myocardial infarction, arrhythmias, angina pectoris, hypertension, hypertensive emergencies, hyperthyroidism and migraine. Paracetamol is an antipyretic agent which is also known for its analgesia and is concurrently administered to patients who are on treatment with propranolol hydrochloride in the management of migraine. Objective: In the present work, an in vitro and in vivo drug interaction was assessed to establish the relationship between drug dissolution and plasma drug concentration and pharmacokinetics of selected drugs. Method: In vitro drug release studies were performed in simulated gastric juice (pH 1.2). The in vitro drug dissolution and changes in plasma concentration of the drugs in vivo in Wistar rats were determined individually and in the presence of other drug at different time interval. Results: A significant delay in the dissolution of propranolol hydrochloride in the presence of paracetamol was observed and the paracetamol dissolution was prolonged in the presence of propranolol hydrochloride. t max of propranolol Hydrochloride was prolonged and extended t 1/2 was found when propranolol hydrochloride was administered with paracetamol concurrently. A delay in t max of paracetamol and shortened t 1/2 was observed. Conclusion: The results show the existence of correlation between in vitro drug dissolution and in vivo plasma concentration and the corresponding pharmacokinetics of propranolol hydrochloride and paracetamol. Key words: Correlation, Drug interaction, In vitro – In vivo , Propranolol hydrochloride, Paracetamol.

Influence of different types of low substituted hydroxypropyl cellulose on tableting, disintegration, and floating behaviour of floating drug delivery systems

The object of the present study is to evaluate the effect of application of low-substituted hydroxypropyl cellulose (L-HPC) 11 and B1 as excipients promoting floating in gastroretentive tablets. Directly compressed tablets were formed based on experimental design. Face-centred central composite design was applied with two factors and 3 levels, where amount of sodium alginate (X1) and L-HPC (X2) were the numerical factors. Applied types of L-HPCs and their 1:1 mixture were included in a categorical factor (X3). Studied parameters were floating lag time, floating time, floating force, swelling behaviour of tablets and dissolution of paracetamol, which was used as a model active substance. Due to their physical character, L-HPCs had different water uptake and flowability. Lower flowability and lower water uptake was observed after 60min at L-HPC 11 compared to L-HPC B1. Shorter floating times were detected at L-HPC 11 and L-HPC mixtures with 0.5% content of sodium alginate, whereas alginate was the only significant factor. Evaluating results of drug release and swelling studies on floating tablets revealed correlation, which can serve to help to understand the mechanism of action of L-HPCs in the field development of gastroretentive dosage forms.

A New Approach to Dissolution Testing by UV Imaging and Finite Element Simulations

Most dissolution testing systems rely on analyzing samples taken remotely from the dissolving sample surface at different time points with poor time resolution and therefore provide relatively unresolved temporally and spatially information on the dissolution process. In this study, a flexible numerical model was combined with a novel UV imaging system, allowing monitoring of the dissolution process with sub second time resolution. The dissolution process was monitored by both effluent collection and UV imaging of compacts of paracetamol. A finite element model (FEM) was used to characterize the UV imaging system. A finite element model of the UV imaging system was successfully built. The dissolution of paracetamol was studied by UV imaging and by analysis of the effluent. The dissolution rates obtained from the collected effluent were in good agreement with the numerical model. The numerical model allowed an assessment of the ability of the UV imager to measure dissolution-time profiles. The simulation was able to extend the experimental results to conditions not easily obtained experimentally. Combining FEM,experimental dissolution data and UV imaging provided experimental validation of the FEM model as well as a detailed description of the dissolution process.

STUDI KOMPARSI TERHADAP LAJU DISOLUSI TABLET PARASETAMOL DENGAN PENAMBAHAN POLISORBAT 80

A study of the dissolution rate of paracetamol tablets using polysorbate 80 as wetting agent had been investigated. The aim of this investigation is to determine concentration of polysorbate 80 should be added to the formula to produced the tablet with the fastest dissolution rate. The paracetamol tablets were prepared by wet granulation methods using polysorbate 80 with various concentration, 1%, 3%, 5%, 7% and 9% respectively. The tablet without polysorbate 80 was also prepared for comparison. The tablets had been evaluated with uniform size, uniform weight, hardness, disintegration time and the dissolution test. The dissolution test of tablet in phosphate buffer pH 5.8 using the stirring paddle with rotation speed at 50 rpm at the temperature 37 ± 0.5°C. The release of paracetamol every time appointed well measured by UV spectrophotometer at wave length 242 nm and the concetration determinated with standard curve. The evaluation of tablets showed that no one formula suitable with requires, the hardness test only formula I suitable with requires and the disintegration time all of the tablet suitable with requires. The result of statistical with complete random form method show the added of polysorbate 80 in the parasetamol tablets formula increase dissolution of paracetamol. The analysis efficiency dissolution using Duncan’s method on data’s showed that the concentration 3% of polysorbate 80 (formula III) give significant effect in increasing the dissolution rate of tablets ( a = 0.05 ). Key word : Polisorbat 80, Dissolition, Paracetamol

The interplay between yam ( Dioscorea sp.) starch botanical source, micromeritics and functionality in paracetamol granules for reconstitution

A comparative investigation of the interplay between starch botanical source, micromeritics and their functionality in formulated paediatric paracetamol granules for reconstitution was conducted using starches extracted from five local yam ( Dioscorea spp. ) species. Significant differences were observed in the physicochemical properties of the different starches studied ( p < 0.05). The observed differences in paracetamol dissolution correlated well with the physicochemical properties of the starches. Granules formulated with Chinese yam and Bitter yam starches showed the fastest rate of paracetamol dissolution with T 80 of 2.2 and 2.6 min, respectively, at 2.5%w/w, and 3.75 and 4.00 min, respectively, at 10% w/w binder concentrations. Those formulated with Round leaf yellow yam starch had the slowest dissolution rate with T 80 of 4.5 and 8.75 min, respectively, at 2.5% and 10% binder concentrations. The results generally indicate a significant dependence of the rate of paracetamol dissolution from granules on starch surface tension, viscosity, swelling power and water binding capacity, particle size distribution, specific surface and porosity. These, in turn, were found to be starch botanic source-dependent suggesting careful consideration of botanic source when substituting one starch product for another in granule formulation.

Tablet disintegration and drug dissolution in viscous media: Paracetamol IR tablets

An investigation into the influence of viscous media on tablet disintegration and drug dissolution was performed with the aim to simulate the potential formulation-specific food effect for a selected highly soluble model drug. Literature data on the in vivo drug absorption in fasted and fed state have been evaluated for in vitro–in vivo correlation (IVIVC) purposes. In vitro studies were conducted in simple buffer media with or without addition of HPMC K4M as a viscosity enhancing agent. Good IVIVC correlation ( r > 0.95) was obtained for paracetamol dissolution in viscous media at 50 rpm and fed state absorption profiles, while in vitro dissolution in simple media at lower stirring speed was predictable of drug products in vivo behaviour in the fasted state. The data obtained support the existing idea that relatively simple dissolution media and/or set of experimental conditions may be used to differentiate formulation-specific food–drug interactions. Such tests would be a useful tool in the development of formulations that would not be susceptible to the influence of co-administered meal and, furthermore, facilitate regulatory decision on the necessity to conduct food effect studies in vivo.

Initial steps of dissolution of monoclinic and rhombic crystals of paracetamol

The initial steps of dissolution of Paracetamol (monoclinic and rhombic modifications) in a series of solvents (10% solutions of acetic anhydride, pyridine, 1,4-dioxane, morpholine, and N-methylmorpholine in CCl4) were studied. The etching patterns on planes parallel and perpendicular to Paracetamol molecular layers were compared.

Dissolution of paracetamol crystallized in the presence of poly(vinyl acetate-co-maleic anhydride)

Copolymer of vinyl acetate and maleic anhydride, poly (vinyl acetate-co-maleic anhydride) was prepared by precipitation polymerization and characterized. Paracetamol was crystallized in presence of different concentrations of poly (vinyl acetate-co-maleic anhydride). Crystals were characterized by sieve analysis, solubility and dissolution study. Crystallization of paracetamol in presence of poly (vinyl acetate-co-maleic anhydride) caused a marked enhancement in its dissolution rate with increase in concentration of poly (vinyl acetate-co-maleic anhydride) in crystallization medium.

The Effect of Selected Water-Soluble Excipients on the Dissolution of Paracetamol and Ibuprofen

The purpose of this investigation was to study the dissolution behavior of paracetamol and ibuprofen in the presence of a range of selected potential excipients. First, a pH-solubility profile was generated for both drugs, and the effect of changing hydrodynamic conditions on the intrinsic dissolution rate was investigated. It was established that both drugs dissolved according to the diffusion-layer model. Paracetamol solubility (approximately 20.3 mg mL− 1) did not vary from pH 1.2–8.0, corresponding to the in vivo range in the gastrointestinal tract. Ibuprofen had an intrinsic solubility of approximately 0.06 mg mL− 1, and pKa was calculated as 4.4. Second, the effects of selected potential excipients (lactose, potassium bicarbonate, sodium bicarbonate, sodium chloride, and tartaric acid) were evaluated by measuring the effect of the inclusion of each additive in the dissolution medium on drug solubility, drug intrinsic dissolution rate, and solution viscosity. The results were evaluated using the diffusion-layer model, and it was determined that for paracetamol, the collected data fitted the model for all the excipients studied. For ibuprofen, it was found that there were differences between the excipients that raised the solution pH above the pKa to those that did not. For the excipients raising the pH above the pKa, the effect on intrinsic dissolution rate was not as high as that expected from the change in drug solubility. It was postulated that this might be due to lack of penetration of the excipient into the drug boundary layer microenvironment. Formulators may calculate the effect of adding an excipient based on solubility increases but may not find the dissolution rate improvement expected.

Dissolution of Extemporaneous Paracetamol Capsules

Aim: To investigate the dissolution characteristics of extemporaneously prepared capsules containing hypromellose and paracetamol tablets.Method: Capsules of varying sizes containing paracetamol (powdered tablets) with varying amounts of hypromellose (4–20% w/w) were extemporaneously prepared. Dissolution was investigated using a USP dissolution testing apparatus. Paracetamol dissolution was quantitated using UV absorption spectrophotometry. The impact of hypromellose content, tablet excipients, capsule size, content weight and mixing methods were investigated.Results: Over a 4‐hour period, paracetamol dissolution decreased with increasing hypromellose content. Paracetamol dissolution was 100% from capsules containing 4% hypromellose and 52 ± 3% from capsules containing 20% hypromellose. Reformulated tablets with different formulations resulted in different dissolution rates. The dissolution rate was faster from small capsules and slower from capsules with a lower content weight. The method used to mix the powders also had a significant effect on the dissolution rate.Conclusion: Modified‐release delivery systems can be extemporaneously prepared from reformulated tablets using hypromellose. Hypromellose content, tablet excipients, capsule size, content weight and mixing methods have an impact on the dissolution rate.J Pharm Pract Res 2004; 34: 276–81.

Evaluation of paracetamol suppositories by a pharmacopoeial dissolution test – comments on methodology

Ph.Eur. and BP have introduced a dissolution apparatus for suppositories. Suitability of the apparatus for quality control of paracetamol suppositories was evaluated and the effect of experimental conditions on dissolution profiles was studied. Paracetamol suppositories containing 80–500 mg of the drug, on fatty base, were obtained from four manufacturers (A, B, C, D). The diffusion cell was modified by incorporation of an in-built thermoprobe and large difference (up to 1.7°C) between temperature in the water-bath and in the dissolution chamber was observed. This effect was avoided by increasing the length of tubing immersed in the thermostat at the inlet of the cell. The most reproducible results were observed for A and C suppositories, however from suppository C the total dose of paracetamol was released after 3.5–4.5 h while the release from suppository A was slow with only 40–87% of the total dose liberated during 6 h. Suppositories B did not melt at 37°C and less than 5% of the drug was released. Fast release was observed after melting when the temperature was elevated to 39.5°C. The results demonstrate clearly that essentially complete melting of a suppository in the dissolution chamber is required for an appropriate dissolution of paracetamol in vitro. Disintegration time, softening time, drop point and particle size of the suspended drug were measured and the relevance of these parameters for dissolution behaviour of the preparations was discussed.

A calorimetric investigation into the interaction between paracetamol and polyethlene glycol 4000 in physical mixes and solid dispersions

The solubility, heat of solution and dissolution rate of paracetamol and polyethyelene glycol 4000 (PEG 4000) systems have been studied in order to clarify the nature of the interaction between the two components during dissolution of solid dispersions. The logarithmic solubility of paracetamol demonstrated a non-linear increase with concentration of PEG 4000, while linear relationships between heat of solution in water and concentration were seen for both individual components. However, the heat of solution of paracetamol was found to decrease with increasing concentrations of PEG 4000. Similarly, the heats of solution in water of physical mixes and solid dispersions prepared using two manufacturing protocols were found to be lower than the theoretical values calculated from those corresponding to the individual components. Drug release studies showed a marked increase in paracetamol dissolution rate when prepared as a solid dispersion, with behaviour consistent with carrier controlled dissolution observed at low drug contents which was ascribed to enhanced dissolution of the drug into the diffusion layer of the PEG 4000. The implications of the understanding of this mechanism for the choice of carrier and manufacturing protocol for solid dispersion products is discussed.

Critical Dissolution Tests of Oral Systems Based on Statistically Designed Experiments. IH. In Vitro/In Vivo Correlation for Multiple-Unit Capsules of Paracetamol Based on PLS Modeling

The main aims of the present study were to establish an in vitro/in vivo correlation/or multiple-unit capsules of paracetamol by means of statistical prediction models and to investigate the effect of a number of in vitro variables on the discussion rate of paracetamol from the formulation. A fractional factorial screening design was used to investigate the effects of the variables agitation, pH, osmolality, viscosity, and the presence of bile salt on the dissolution rate of paracetamol. The effects were evaluated in two separate partial least-squares models, in which the responses were expressed as the cumulative percentage of paracetamol dissolved at specified time-points (model I) and as the shape (β) and scale (η) parameters according to the Weibull function (model II).It was concluded that agitation and viscosity had significant effects on the dissolution rate of paracetamol. Statistical models based on the responses from models I and II were then used to predict the in vitro conditions most closely correlated with the in vitro dissolution of paracetamol after administration of the formulation to 10 healthy volunteers. The predicted optimal in vitro conditions were similar for the two models and not too far from what is expected from the gastrointestinal tract. The experimental verification of the in vitro conditions showed that both models were equally good, and contributed to high degrees of correlation with the in vivo dissolution behavior of the formulation during 9 hr. The relationships obtained when plotting the percentage dissolved in vitro versus in vivo were y - 1.1x (r2 = 0.98) and y = 1.1x (r2 = 0.94) for models I and II, respectively. Based on these results, it is difficult to state a preference for one of the models. Finally, the use of statistical prediction models to develop critical in vitro tests is a successful approach in the establishment of associations between dissolution behavior in vitro and in vivo for oral extended-release systems.