Studies on Controlled-Release Formulations of Diclofenac Sodium

Abstract

The effects of various polymers on the release of diclofenac sodium from their matrices have been evaluated. In vitro release profiles of diclofenac sodium from ethylcellulose and hydroxypropylmethylcellulose (HPMC) K4M matrices showed that decreasing the concentration of ethylcellulose and increasing the concentration of HPMC K4M resulted in an increase in the release rate of diclofenac sodium. An increase in the amount of lactose in matrix resulted in an increase in the release rate of diclofenac sodium. It is suggested that the use of ethylcellulose or Precirol containing relatively large percentage concentrations of lactose in matrices will not provide zero-order release of diclofenac sodium from matrices. The best-fit release kinetics with the highest correlation coefficients was achieved with the Higuchi's plot followed by the zero-order. A straight line relationship was established bemeen the T_50% and the ratio of HPMC K4M to diclofenac sodium.     

Impact of polymers on the aggregation of wet-milled itraconazole particles and their dissolution from spray-dried nanocomposites

We explore the impact of various polymers and their molecular weight on the stabilization of wet-milled suspensions of itraconazole (ITZ), a poorly soluble drug, and its dissolution from spray-dried suspensions. To this end, ITZ suspensions with SSL, SL, and L grades of hydroxypropyl cellulose (HPC) having molecular weights (MWs) of 40, 100, and 140?kg/mol, respectively, hydroxypropyl methyl cellulose (HPMC E3 with 10?kg/mol), polyvinylpyrrolidone (PVP K30 with 50?kg/mol), sodium dodecyl sulfate (SDS, surfactant), and HPC SL–SDS were wet media milled and spray-dried. Laser diffraction results show that 2.5% HPC SL–0.2% SDS led to the finest ITZ nanosuspension, whereas without SDS, only 4.5% HPC with SL/L grades ensured minimal aggregation. Rheological characterization reveals that aggregated suspensions exhibited pronounced pseudoplasticity, whereas stable suspensions exhibited near Newtonian behavior. Spray-drying yielded nanocomposites with 60–78% mean ITZ loading and acceptable content uniformity. Severe aggregation occurred during milling/drying when 4.5% polymers with MW?≤?50?kg/mol were used; their nanocomposites exhibited incomplete redispersion due to slow matrix erosion and released ITZ slowly during dissolution test. Overall, high drug-loaded, surfactant-free ITZ nanocomposites that exhibited immediate release (>80% dissolved in 20?min) were prepared via spray-drying of wet-milled ITZ with 4.5% HPC SL/L.     

Solubility advantage from amorphous etoricoxib solid dispersions

Objective: This study aimed to evaluate kinetic solubility advantage of amorphous etoricoxib solid dispersions prepared with three water soluble polymers and correlate it with solid state and supersaturated drug solution stabilization potential of these polymers.

Methods: Amorphous solid dispersions (ASDs) of etoricoxib were prepared with polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and hydroxyethyl cellulose (HEC) at 70:30w/w ratio and characterized for glass transition temperature (T_g), miscibility and intermolecular interactions. Kinetic solubility profiles of amorphous etoricoxib and its ASDs were determined in water at 37 °C. Solid-state stability was assessed by enthalpy relaxation studies at a common degree of undercooling of around 19.0 °C at 0% RH. Recrystallization behavior of supersaturated drug solution was evaluated in the absence and presence of pre-dissolved polymer at 37 °C.

Results: Amorphous etoricoxib exhibited rapid solid-to-solid transition to yield a solubility advantage of merely 1.5-fold in water. Among the ASDs, etoricoxib-PVP dispersion exhibited maximal “peak” (2-fold) and “plateau” (1.8-fold) solubility enhancement, while etoricoxib-PVA dispersion could only sustain the “peak” solubility achieved by amorphous etoricoxib. In contrast, etoricoxib-HEC dispersion displayed no solubility advantage. The rank order for solid state and supersaturated solution stabilization followed a similar trend of amorphous etoricoxib?Conclusion: Dissolution behavior of ASDs is influenced by concomitantly occurring solid phase changes, thus understanding these processes independently can enable assessment of the predominant route of drug crystallization and stabilization by the polymer.     

Compatibility Studies Between Ibuprofen or Ketoprofen with Cellulose Ether Polymer Mixtures Using Thermal Analysis

ABSTRACT

Differential scanning calorimetry (DSC) was used to investigate and detect incompatibilities between drugs such as: ibuprofen (IBU) or ketoprofen (KETO) with cellulose ether derivatives, which are frequently applied on controlled release dosage forms. Binary mixtures concerning methylcellulose (MC25) or hydroxypropylcellulose (HPC) with hydroxypropylmethylcellulose (HPMC) K15M or K100M in different ratios were prepared and evaluated by the appearance, shift, or disappearance of peaks and/or variations in the corresponding ΔH values. According to the DSC results, binary mixtures between those polymers were found to be compatible, but their mixture with IBU or KETO, promotes a solid–solid interaction mainly with 1:1:1 (w/w) ratio (drug-excipient). However, when the drug:excipient interactions were detected, they were not found to affect the drug bioavailability. DSC was successfully employed to evaluate the compatibility of the drugs with the selected polymers.     

Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion

ABSTRACT

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop®. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630®), and ethyl acrylate, methyl methacrylate polymer (Eudragit® EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T_gs were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N–H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit® EPO solid dispersion and Nimotop®, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC_{0–12 hr} values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

In vitro release of ketoprofen from hydrophilic matrix tablets containing cellulose polymer mixtures

The effect of cellulose ether polymer mixtures, containing both hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC K15M or K100M), on ketoprofen (KTP) release from matrix tablets was investigated. In order to evaluate the compatibility between the matrix components, Raman spectroscopy, scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD) experiments were performed. The results evidence the absence of significant intermolecular interactions that could eventually lead to an incompatibility between the drug and the different excipients. Formulations containing mixtures of polymers with both low and high viscosity grades were prepared by a direct compression method, by varying the polymer/polymer (w/w) ratio while keeping the drug amount incorporated in the solid dispersion constant (200?mg). The hardness values of different matrices were found within the range 113.8 to 154.9 N. HPLC analysis showed a drug content recovery between 99.3 and 102.1%, indicating that no KTP degradation occurred during the preparation process. All formulations attained a high hydration degree after the first hour, which is essential to allow the gel layer formation prior to tablet dissolution. Independent-model dissolution parameters such as t_10% and t_50% dissolution times, dissolution efficiency (DE), mean dissolution time (MDT), and area under curve (AUC) were calculated for all formulations. Zero-order, first-order, Higuchi, and Korsmeyer–Peppas kinetic models were employed to interpret the dissolution profiles: a predominantly Fickian diffusion release mechanism was obtained – with Korsmeyer–Peppas exponent values ranging from 0.216 to 0.555. The incorporation of HPC was thus found to play an essential role as a release modifier from HPMC containing tablets.     

Effects of Cellulose Derivatives and Additives in the Spray-Drying Preparation of Acetaminophen Delivery Systems

Microcrystalline cellulose (MCC), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypro pylcellulose (HPC), and ethylcellulose (EC) were used for the production of time-controlled acetaminophen delivery systems using a spray-drying technique. The influence of factors such as polymer concentration, inlet temperature, and drug/polymer ratio were investigated. The product yields were a function of the type and concentration of the polymer, with the highest values being reached from feeds containing 1% MCC and EC. Parameters of 1% polymer concentration and an inlet temperature of 140°C gave rise to optimal processing conditions. Using these parameters, the influence of some adjuncts, such as polyethylene glycol 6000 (PEG 6000), dibutyl sebacate (DBS), polyvinylpyrrolidone (PVP), and carboxylic acids such as citric acid (CA), phthalic acid (PA), succinic acid (SA), tartaric acid (TA), and oxalic acid (OA), on the spray-drying process was evaluated. Of the additives tested, PVP (with MCC), DBS (with EC), and PEG 6000 (with NaCMC) induced yield decreases from 70% to 49%, 66% to 39%, and 37% to 17%, respectively. As for carboxylic acids (with NaCMC), similar or better performances of 43%, 45%, 47%, and 49% were obtained with SA, OA, PA, and TA, respectively. Dissolution studies in pH 1 dilute HCl and pH 6.8 phosphate buffer dissolution media showed that formulations consisting of 1% polymer with a drug/polymer ratio of 1/1 exhibited the slowest drug release, with the spheroids coated with NaCMC and HEC showing the longest T_50% values (with 45 and 53 min at pH 1 and 49 and 55 min at pH 6.8, respectively). Slightly better sustained drug release in pH 6.8 dissolution medium was reached, showing the following trend: HEC > NaCMC > MCC > EC > HPMC. Concerning the additives, the trends in dissolution T_50% of drug revealed TA > SA > CA > OA > PVP > PA > DBS in acidic pH 1 dissolution medium and PVP > OA > TA > SA > PA > CA > DBS in phosphate buffer at pH 6.8.     

In Vitro and In Vivo Adhesion Testing of Mucoadhesive Drug Delivery Systems

Bioadhesive tablets were prepared by physical mixing of polymers and drug, then granulating and compressing into a tablet. The mucoadhesion was evaluated by shear stress measurement, detachment force measurement, and X-ray photography of the rabbit gastrointestinal tract. The strong interaction between the polymer and the mucous lining of the tissue helps increase contact time and permit localization. Polymers like hydroxypropyl methylcellulose K4M (HPMC K4M), hydroxypropyl methylcellulose 100 cps (HPMC 100 cps), carbopol-934, sodium carboxy methylcellulose (Na CMC), guar gum, and polyvinylpyrrolidone (PVP) were tested by shear stress measurement and detachment force measurement methods. HPMC K4M, showing maximum bioadhesion, was used in further studies. Adhesion was maximum between pH 5 and pH 6. Maximum adhesion was observed in the duodenum, followed by the jejunum and ileum. Barium sulfate (BaSO₄) matrix tablets containing polymer and drug were subjected to X-ray studies in rabbits, and it was found that the tablet was mucoadhesive even after 8 hr. Enteric coating did not show any effect on mucoadhesion after passing from the stomach.     

Daidzein/cyclodextrin/hydrophilic polymer ternary systems

Objective: To evaluate the effect of different cyclodextrins (β-cyclodextrin [β-CD], methyl-β-cyclodextrin [Mβ-CD], or hydroxypropyl-β-cyclodextrin [HPβ-CD]) and/or hydrophilic polymers (carboxymethylcellulose, hydroxypropylmethylcellulose [HPMC], polyethyleneglycol, or polyvinylpyrrolidone [PVP]) on daidzein solubility in water.

Materials and methods: The corresponding associations were characterized in aqueous media using phase-solubility studies. The morphology of daidzein/cyclodextrin freeze-dried complexes was characterized using scanning electron microscopy, and their spatial configuration was proposed by means of nuclear magnetic resonance spectroscopy.

Results and discussion: In the presence of 6?mM of cyclodextrins, the solubility of daidzein in water was significantly enhanced: 5.7-fold (β-CD), 7.2-fold (Mβ-CD), and 9.4-fold (HPβ-CD). The analysis of the three solid complexes proved that the formation of inclusion complexes occurred through the insertion of the B and C rings of daidzein molecule into the cyclodextrins cavity. The association of daidzein/cyclodextrin complexes to the hydrophilic polymers HPMC or PVP (1%, w/w) was able to improve the solubility of daidzein even further.

Conclusion: The highest solubilizing effect was obtained for daidzein/HPβ-CD/PVP ternary system (12.7-fold).     

Influence of water-soluble polymers on the in vitro performance of floating mucoadhesive tablets containing metformin

Context: The in vitro performance of floating mucoadhesive metformin tablets was optimized using different polymer ratios of polyvinylpyrrolidone (PVP) tamarind seed gum (TSG) and hydroxypropylmethylcellulose (HPMC).

Objective: The objectives of this investigation were to investigate the combinatorial effects of PVP, TSG and HPMC; to study the work of adhesion measured on stainless steel (W_ss) and on rabbit gastric mucosa (W_gm); and a comparison of hydrophilic and more hydrophobic tablets.

Material and methods: In vitro performance was measured as tablet hardness (H), tablet floating lag time (FLT), time needed to release 60% of drug content (t_60%), swelling thickness (S), W_ss and W_gm. To compare the effects, a simplex lattice mixture design was used.

Results and discussion: H, FLT, W_ss and W_gm were found dependent on polymer ratio. H was increased when PVP ratio was increased. FLT, W_ss and W_gm were increased when HPMC ratio was increased. The p value for the lack of fit for all models were greater than 0.05. An approximate linear correlation between W_gm and W_ss was established (R²?=?0.71). The tablets containing PVP resulted in larger H, shorter FLT and t_60%, whereas W_ss and W_gm were enhanced.

Conclusion: The different in vitro performance of tablets containing different water-soluble polymers could be explained partially by the differences in the hydrophilic properties of the polymers and the ability of PVP to interact with HPMC or TSG. An equation established is used to conclude mucoadhesion based on adhesion measurements on stainless steel.     

Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

Preparation and characterization and release properties of Eudragit RS based ibuprofen pellets prepared by extrusion spheronization: effect of binder type and concentration

Objective: The effects of type and concentration of binding agent on properties of Eudragit RS based pellets were studied.

Materials and methods: Pellets containing ibuprofen (60%), Eudragit RS (30%), Avicel (10%) were prepared by extrusion spheronization. PVP K30, PVP K90, HPMC 6cp, HPMC K100LV or HPMC K4M were used as binders in concentrations of 2, 4 or 6% based on the total weight of formulation. The process efficiency, pellet shape, size distribution, crushing strength, elastic modulus and drug release were examined. The effect of curing on pellet properties was also investigated.

Results: The process of extrusion spheronization became difficult with increase in binder viscosity and/or concentration. An increase in binder viscosity and/or concentration resulted in reduction in the yield of pellets, wider particle size distribution and departure from spherical shape especially in the case of HPMC binder. The crushing strength and elastic modulus of pellets decreased with increase in PVPs concentration. However this was not the case for pellets containing HPMCs. Drug release rate increased as the concentration of binder increased. Pellets containing 2%w/w of PVP K30 showed the slowest release rate. For those pellets with brittle nature, curing changed the behavior of pellet under mechanical test to plastic deformation. Yield point and elastic modulus of all formulations decreased after curing. Curing decreased the drug release rate.

Conclusion: Binder type and concentration significantly affected the properties of pellets. For production of sustained release ibuprofen Eudragit RS based pellets lower viscosity binders (PVP K30) with concentrations less than 4%w/w was optimum.     

Study of controlled-release floating tablets of dipyridamole using the dry-coated method

Dipyridamole (DIP), having a short biological half-life, has a narrow absorption window and is primarily absorbed in the stomach. So, the purpose of this study was to prepare controlled-release floating (CRF) tablets of dipyridamole by the dry-coated method. The influence of agents with different viscosity, hydroxypropylmethylcellulose (HPMC) and polyvinylpyrollidon K30 (PVP K30) in the core tablet and low-viscosity HPMC and PVP K30 in the coating layer on drug release, were investigated. Then, a study with a three-factor, three-level orthogonal experimental design was used to optimize the formulation of the CRF tablets. After data processing, the optimized formulation was found to be: 80?mg HPMC K4M in the core tablet, 80?mg HPMC E15 in core tablet and 40?mg PVP K30 in the coating layer. Moreover, an in vitro buoyancy study showed that the optimized formulation had an excellent floating ability and could immediately float without a lag time and this lasted more than 12?h. Furthermore, an in vivo gamma scintigraphic study showed that the gastric residence time of the CRF tablet was about 8?h.     

Selection of excipient,solvent and packaging to optimize the performance of spray-dried formulations: case example fenofibrate

Context: Along with other options, solid dispersions prepared by spray drying offer the possibility of formulating poorly soluble drugs in a rapidly dissolving format. As a wide range of potential excipients and solvents is available for spray drying, it is usually necessary to carry out a comprehensive array of studies to arrive at an optimal formulation.

Objective: To study the influence of formulation parameters such as co-sprayed excipients, solvents and packaging on the manufacture, in vitro performance and stability of spray-dried oral drug products using fenofibrate as a model drug.

Materials and methods: Solid dispersions of fenofibrate with different amorphous polymers were manufactured from two solvent systems by spray drying. These were characterized in terms of physicochemical properties, crystalline content and dissolution behavior in biorelevant media upon production and after storage in two packaging systems (Glass and Activ-Vials^?).

Results and discussion: Spray drying the same formulation from two different solvents led to different physicochemical properties, dissolution behavior and long-term stability. The dissolution behavior and long-term stability also varied significantly among excipients. The viscosity of the polymer and the packaging material proved to be important to the long-term stability.

Conclusion: For spray-dried products containing fenofibrate, the excipients were ranked according to dissolution and stability performance as follows: PVP derivatives >> HPMC 2910/15, HPMCAS-MF, HP-β-CD >> PVP:PVA 2:8. EtOH 96% proved superior to acetone/water for spray drying with polymers. The results were used to propose a general approach to developing spray-dried formulations of poorly soluble drugs.     

Design and optimization of gastric floating sustained-release mini-tablets of alfuzosin hydrochloride based on a factorial design: in vitro/in vivo evaluation

Abstract

The purpose of this research was to develop multiple-unit gastric floating mini-tablets and to evaluate the possibility of using these mini-tablets as a delivery system to improve the drug absorption for drugs with a narrow absorption window. Mini-tablets were prepared using hydroxypropyl methylcellulose (HPMC K100M) and carbopol 971P as release retarding agents and sodium bicarbonate (NaHCO₃) as gas-forming agent. The properties of the prepared mini-tablets in terms of floating characteristic parameters and in vitro release were evaluated. Furthermore, in vivo gastric retention study in rats and in vivo pharmacokinetic study in rabbits of the optimized formulation were performed. The optimized mini-tablets containing 45% HPMC K100M, 15% stearyl alcohol, 13% carbopol 971P, and 12% NaHCO₃ were found to float immediately within 1?min and duration more than 9?h. The in vivo gastric retention study results indicated that the mini-tablets could retain in the stomach for more than 6.67?h. Furthermore, the AUC_0?t of the floating mini-tablets (6849.83?±?753.80?h ng·mL^?1) was significantly higher than that of marketed sustained-release tablets XATRAL®XL (4970.16?±?924.60?h ng·mL^?1). All these results illustrated that the gastric floating mini-tablets might be a promising drug delivery system for drugs with a narrow absorption window.     

Interconversion Kinetic Studies of Betamethasone Acetate Polymorphs in Water

ABSTRACT

This study assessed the effect of polymers on the transformation of polymorphs of betamethasone acetate (BA) when suspended in water. The results showed that the polymers, in particular HPMC E5, retarded the transition of the forms Iα and Iβ. However, the form Iα, as the metastable form, with the aid of HPMC E5, was preferred for BA suspension preparation through kinetic studies, while the form Iβ was not suitable due to its instability in water.     

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Sustained Release Tablet Formulation for a New Iron Chelator

Abstract

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Symbolic regression via genetic programming in the optimization of a controlled release pharmaceutical formulation

Symbolic regression via genetic programming (GP) was used in the optimization of a pharmaceutical zero-order release matrix tablet, and its predictive performance was compared to that of artificial neural network (ANN) models. Two types of GP algorithms were employed: 1) standard GP, where a single population is used with a restricted or an extended function set, and 2) multi-population (island model) GP, where a finite number of populations is adopted. The amounts of four polymers, namely PEG4000, PVP K30, HPMC K100 and HPMC E50LV were selected as independent variables, while the percentage of nimodipine released in 2 and 8 h (Y_2h, and Y_8h), respectively, and the time at which 90% of the drug was dissolved (t_90%), were selected as responses. Optimal models were selected by minimization of the Euclidian distance between predicted and optimum release parameters. It was found that the prediction ability of GP on an external validation set was higher compared to that of the ANNs, with the multi population and standard GP combined with an extended function set, showing slightly better predictive performance. Similarity factor (f₂) values confirmed GP's increased prediction performance for multi-population GP (f₂ = 85.52) and standard GP using an extended function set (f₂ = 84.47).