Osmotic Tablets Research Articles

Microfabrication of controlled release osmotic drug delivery systems assembled from designed elements

ABSTRACT Background This study investigates combining 3D printing with traditional compression methods to develop a multicomponent, controlled-release drug delivery system (DDS). The system uses osmotic tablet layers and a semipermeable membrane to control drug release, similar to modular Lego® structures. Methods The DDS comprises two directly compressed tablet layers (push and pull) and a semipermeable membrane, all contained within a 3D-printed frame. The membrane is made from cellulose acetate and plasticizers like glycerol and propylene glycol. Various characterization techniques, including Positron Annihilation Lifetime Spectroscopy (PALS), were employed to evaluate microstructural properties, wettability, morphology, and drug dissolution. Results Glycerol improved the membrane’s wettability, as confirmed by PALS. The system achieved zero-order drug release, unaffected by stirring rates, due to the push and pull tablets within the 3D-printed frame. The release profile was stable, demonstrating effective drug delivery control. Conclusion The study successfully developed a prototype for a controlled-release osmotic DDS, achieving zero-order release kinetics for quinine hydrochloride after 2 h. This modular approach holds potential for personalized therapies in human and veterinary medicine, allowing customization at the point of care.

OSMOTIC DRUG DELIVERY SYSTEM OF NICORANDIL: DESIGN AND EVALUATION

Objective: The purpose of the current research was to design a nicorandil formulation with controlled drug release using the principles of osmotic pump technology. Nicorandil is a biopharmaceutical classification system (BCS) class 3 drug, having a shorter plasma elimination half-life and bioavailability of 75 to 80%. Methods: The elementary osmotic pump (EOP) was prepared by coating a cellulose acetate polymer on the prepared core tablet. A 24-factorial design was applied to optimize the parameters for the osmotic tablet. A surface orifice was drilled. Results: Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) results showed that there was no interaction between drugs and excipients. A 24-factorial design was applied to optimize the parameters for the elementary osmotic pump. The optimized batch was characterized for in vitro drug release studies, and the effects of pH, osmotic pressure, and agitation intensity were analyzed. All the batches showed a drug release ranging from 90.48% to 98.78% after 12 hours. There was no change in the drug release pattern at different pHs and agitation intensities. The drug release was found to decrease with the increasing osmotic pressure of the dissolution medium. The results showed that the amounts of sodium chloride and mannitol were positively affecting the drug release, while the plasticizers PEG400 and DBP were not critical. Scanning electron microscopic studies (SEM) showed the integrity and surface morphology of the coating membrane before and after dissolution. The prepared EOP was found to deliver nicorandil at zero-order for up to 12 hours. Conclusion: Nicorandil was developed successfully as a controlled drug delivery during a 12-hour period, with variables optimized by the use of a 24-factorial design.

Design, optimization, and characterization of an in-situ pore-forming system for controlled delivery of paliperidone

The purpose of the current investigation was to develop a pharmaceutical equivalent osmotic drug delivery formulation of Paliperidone (PLD) in the form of controlled porosity osmotic pump tablets (CPOT) in order to keep the drug's steady state concentration in the body. This helps to achieve the greatest therapeutic benefit with the fewest side effects. For the purpose of identifying various formulation attributes, preliminary trials were conducted. Taguchi design was used to study the influence of seven input factors namely drug to polymer ratio, polymer 1(HPMC K100 M) to polymer 2 (HPMC K15 ​M), drug to total osmogens, coating level, amount of pore former, concentration of ethyl cellulose and amount of plasticizer on dependent variable similarity factor (f2). Utilizing the Minitab 17, data analysis was done. The similarity factor (f2) was computed using the osmotic tablet reference product INVEGA®. The findings demonstrate that each of the seven independent variables significantly affects the similarity factor. For optimized batch, both core and coated tablets showed acceptable pharmaco-technical parameters. The release profile of the optimized batch tablets was found to be similar to that of reference product with good zero-order release pattern. Drug release was observed through the channels formed by in-situ pores on tablet surface performed using SEM. From the results it can be concluded that prepared CPOT of PLD was found pharmaceutical equivalent with commercial product which is cost effective and fully compliance with cGMP.

Development and Characterization of Rivastigmine Hydrogen Tartrate Elementary Osmotic Tablets

Development and Characterization of Rivastigmine Hydrogen Tartrate Elementary Osmotic Tablets

Industry Update, October 2022.

Industry Update, October 2022.

Nateglinide Modified Release Dosage Form Using Elementary Osmotic Pump and Push Pull Osmotic Pump Methods: Formulation and in-vivo evaluation

Objective: The aim was to develop osmotic tablets of nateglinide by two methods namely elementary osmotic pump (EOP) and push-pull osmotic pump (PPOP) method for controlled drug release.
 Methods: The tablets were prepared by the wet granulation and were evaluated for various physicochemical parameters, in-vitro dissolution and in-vitro dissolution. The optimised formulation obtained in both methods was further characterised for FTIR, stability studies and pharmacokinetic studies.
 Results: In EOP method coated tablet F14 showing highest drug release of 98.82%. In PPOP formulation FF14 was optimized with highest drug release of 99.97% and also its granules were having better flow property. Both F14 and FF14 were further characterized for FTIR, which showed no significant interaction and the accelerated studies indicated formulations were stable for 3months. The in-vivo studies in rabbits revealead Cmax of the optimised formulation (FF14) was 469.67±0.034 ng/ml, and the Cmax of the marketed product was 401.27±0.08 ng/ml. The Tmax of the formulation and the pure drug were 6.0±0.07 h and 1.5±0.04 h, respectively. The AUC0-infinity of the FF14 was higher ((2829.83±1.47 ng.h/ml) than the marketed suspension (1310.62±0.82 ng.h/ml). The AUC0-t of the FF14 formulation was significantly higher than that of the marketed product (p<0.05).
 Conclusion: A better improvement in-vitro dissolution profile and bioavailability of the osmotic tablet of nateglinide was observed using PPOP method.

Osmotic Pump Drug Delivery Systems-A Comprehensive Review.

In the last couple of years, novel drug delivery systems (NDDS) have attracted much attention in the food and pharmaceutical industries. NDDS is a broad term that encompasses many dosage forms, one of which is osmotic pumps. Osmotic pumps are considered to be the most reliable source of controlled drug delivery, both in humans and in animals. These pumps are osmotically controlled and release active agents through osmotic pressure. To a large extent, drug release from such a system is independent of gastric fluids. Based on such unique properties and advantages, osmotic pumps have made their mark on the pharmaceutical industry. This review summarizes the available osmotic devices for implantation and osmotic tablets for oral administration.

SeDeM tool-driven full factorial design for osmotic drug delivery of tramadol HCl: Formulation development, physicochemical evaluation, and in-silico PBPK modeling for predictive pharmacokinetic evaluation using GastroPlus™.

The study is based on using SeDeM expert system in developing controlled-release tramadol HCl osmotic tablets and its in-silico physiologically based pharmacokinetic (PBPK) modeling for in-vivo pharmacokinetic evaluation. A Quality by Design (QbD) based approach in developing SeDEM-driven full factorial osmotic drug delivery was applied. A 24 Full-factorial design was used to make the trial formulations of tramadol HCl osmotic tablets using NaCl as osmogen, Methocel K4M as rate controlling polymer, and avicel pH 101 as diluent. The preformulation characteristics of formulations (F1-F16) were determined by applying SeDeM Expert Tool. The formulation was optimized followed by in-vivo predictive pharmacokinetic assessment using PBPK “ACAT” model of GastroPlus™. The FTIR results showed no interaction among the ingredients. The index of good compressibility (ICG) values of all trial formulation blends were ≥5, suggesting direct compression is the best-suited method. Formulation F3 and F4 were optimized based on drug release at 2, 10, and 16 h with a zero-order kinetic release (r 2 = 0.992 and 0.994). The SEM images confirmed micropores formation on the surface of the osmotic tablet after complete drug release. F3 and F4 were also stable (shelf life 29.41 and 23.46 months). The in vivo simulation of the pharmacokinetics of the PBPK in-silico model revealed excellent relative bioavailability of F3 and F4 with reference to tramadol HCl 50 mg IR formulations. The SeDeM expert tool was best utilized to evaluate the compression characteristics of selected formulation excipients and their blends for direct compression method in designing once-daily osmotically controlled-release tramadol HCl tablets. The in-silico GastroPlus™ PBPK modeling provided a thorough pharmacokinetic assessment of the optimized formulation as an alternative to tramadol HCl in vivo studies.

Effect of Coating Thickness and Polyethylene Glycol’s Molecular Weight on Diltiazem Hydrochloride Release from Controlled Porosity Osmotic Pump Tablets

The purpose of this research was to design CPOP tablets to achieve controlled delivery of diltiazem hydrochloride (DH) up to 12 hours, which is a water-soluble calcium channel blocker with a short biological half-life. Two batches of osmotic tablet cores were prepared, containing DH with mannitol as an osmotic agent (1: 1.5 ratio). The tablet cores formulation with 10 mm diameter achieved the required technical and mechanical specifications. Direct compression technique was used to prepare the tablet cores which were evaluated in terms of mechanical resistance and uniformity of dosage units, followed by spray film coating using cellulose acetate as a former polymer of the semipermeable membrane and polyethylene glycol (PEG) as a pore forming agent. Several molecular weights of PEG (6000, 1500 and 400) were used and coating thickness levels were obtained. In vitro drug release, morphology of coating surface and the effect of pH change on release rate were investigated. Most of the prepared formulations demonstrated a burst release at the initial stage, which could be controlled by increasing the coating thickness. Formulations with PEG400 as a pore former presented better controlled and less burst release than those containing PEG6000, PEG1500, or a mixture of PEG6000: PEG400 (1: 1), and the pH change did not affect the drug release except in the initial stage.

Formulation Optimization and Evaluation of Push Pull Osmotic Pump Tablet of Vildagliptin

Purpose- The present study was to develop an oral push-pull osmotic pump tablet of vildagliptin, DPP-IV inhibitor drug; which is BCS class I drug. Method- The tablets were prepared by the wet granulation method using polyox and osmotic agent NaCl. The granules were compressed into bilayered tablet by conventional compression machine. The bilayered core osmotic tablets were coated with cellulose acetate in a conventional pan coating. In-vitro dissolution was evaluated using USP dissolution apparatus II in 0.1 N HCl pH 1.2 buffers for 2 hrs and phosphate buffer pH 7.5 for 22 hrs respectively. The formulated optimized batch VP1 were kept to stability studies for 3 months. Result- The formulated optimized batch VP1 of PPOP tablet shows 2hrs lag time with zero order release kinetic. In –vitro drug release was obtained 91.45 % up to 22hrs respectively. Polyox in push-pull layer along with osmotic agent and cellulose acetate controlled the drug release pattern from formulated PPOP tablet. No significant changes were observed upto the period of 3 months of storage during stability study. Conclusion- The PPOP tablet of vildagliptin was able to deliver the drug in controlled pattern over a long period of time by the process of osmosis. Conventional compression and pan coating method can be used to prepare PPOP tablet successfully.

Formulation development and evaluation of osmotic drug delivery system for lornoxicam

Osmotic systems are the most reliable controlled drug delivery systems and can be employed as oral drug delivery systems. Osmotic pressure is used as the driving force for these systems to release the drug in a controlled manner. Osmotic pump tablet (OPT) generally consists of a core including the drug(s), an osmotic agent, other excipients and semipermeable membrane coat. The aim of current study was to develop osmotic drug delivery system for Lornoxicam. Two different approaches were used for formulation, one was controlled porosity osmotic tablet and other was elementary osmotic tablet. The formulations were evaluated for different parameters like appearance, uniformity of weight, drug content, hardness and drug release also the effect of different osmotic agents responsible for developing the osmotic pressure such as sodium chloride and mannitol along with different concentration of pore former sorbitol were studied and comparison was made between first controlled porosity osmotic tablet which include the osmotic tablet in which coating membrane contains water soluble pore forming polymers when the membrane comes in contact with water the leaching of polymers occur thereby permitting the water inside the wall and creating the osmotic pressure to release the drug and second the elementary osmotic tablet containing osmotic agent sodium chloride coated with the rate controlling semipermeable membrane of cellulose acetate, this membrane contains an orifice of a critical size through which the drug is delivered. From the results it was found that the developed formulation the controlled porosity osmotic tablet of Lornoxicam (CPOP) was able to release the drug over 12 hrs at zero order and also the concentration of osmotic agent, level of pore former and thickness of coating membrane are responsible for controlling the release of Lornoxicam. The coating membrane was subjected to SEM analysis which showed formation of pores in the membrane. The developed controlled porosity osmotic pump tablet of lornoxicam was found to control the release for 12 hrs.

Optimization of Repaglinide Osmotic Drug Delivery System Using Two Different Techniques

The current study aimed to formulate an elementary osmotic pump (EOP) and push-pull osmotic pump (PPOP) based drug delivery system for controlled release of an anti-diabetic agent, repaglinide is expected to provide sustained release. EOP and PPOP method prepared repaglinide tablets by wet granulation technique. EOP designed 15 formulations F1-F15 and 14 formulations were done by PPOP method. All the formulations were evaluated for various physicochemical parameters and in-vitro dissolution studies. The release data was fitted into mathematical kinetic modeling studies to check the release mechanism. Further, the optimized formulations from both methods were characterized by FTIR and stability studies. EOP and PPOP methods successfully prepared repaglinide osmotic tablets. All the formulations exhibitedb satisfactory results for all evaluated parameters. The highest drug release was exhibited from F15 prepared by EOP method with 99.76% and FF14 with 15% coating prepared by PPOP method with drug release of 99.73%. Based on the in vitro dissolution profile, formulation F15 and FF14 exhibited zero-order with Korsmeyer-Peppas kinetics with Fickian diffusion-controlled release mechanism with high drug release in 24 hours and hence were selected as optimized formulations. The drug-excipient compatibility study by FTIR indicated no significant interactions between drugs and excipients. The formulations were stable after 3 months of accelerated stability studies. EOP and PPOP were designed to effectively administrate repaglinide drugs for a prolonged period of time.

Osmotic tablet coatings: Drying stress, mechanical properties and microstructure

The coatings in osmotic tablets play a critical role in controlling the release of active pharmaceutical ingredient. Coatings are formed by spraying dilute polymer solution onto the tablet surface. During drying, the films develop shrinkage stress, which can cause cracking. The coatings are also subject to large tensile stress generated by osmotic pressure during the dissolution process, which may rupture the coating. Despite the role of tensile stress in causing fracture in osmotic tablet coatings, a rigorous quantification of the drying stress, mechanical properties and microstructure is missing. The present work fills this gap via detailed measurement of drying stress, Young’s modulus and fracture properties of osmotic tablet coatings of cellulose acetate mixed with two different plasticisers, namely polyethylene glycol and hydroxypropyl cellulose. The measurements were complemented with imaging of the surface and the cross-section of films using scanning electron microscopy so as to relate the drying stress and mechanical properties to the microstructure of the films. The phase separation during the drying process increases the pore size, while simultaneously decreasing the modulus and the peak drying stress of the drying films. The results suggest that films with strong adhesion to the tablet surface will not rupture but if the films delaminate, the drying stress are sufficiently large to cause rupture. The detailed study presented here provides guidelines to the formulator for designing rupture-free osmotic coatings.

Topologically directed confocal Raman imaging (TD-CRI): Advanced Raman imaging towards compositional and micromeritic profiling of a commercial tablet components

Particle size distribution (PSD), spatial location and particle cluster size of ingredients, polymorphism, compositional distribution of a pharmaceutical product are few of the most important attributes in establishing the drug release-controlling microstructural and solid state properties that would be used to (re)design or reproduce similar products. There are numerous solid-state techniques available for PSD analysis. Laser diffraction (LD) is mostly used to study PSD of raw materials. However, a constraint of LD is the interference between the active pharmaceutical ingredients (API) and excipients, where it is very challenging to measure API size in a tablet. X-ray powder diffraction (XRPD) is widely employed in establishing the polymorphism of API and excipients. This research examined a commercial osmotic tablet in terms of extracting solid state properties of API and functional excipient by Raman Imaging. Establishing repeatability, reproducibility, and sample representativeness when the samples are non-uniform and inhomogeneous necessitates multiple measurements. In such scenarios, when employing imaging-based techniques, it can be time-consuming and tedious. Advanced statistical methodologies are used to overcome these disadvantages and expedite the characterization process. Overall, this study demonstrates that Raman imaging can be employed as a non-invasive and effective offline method for assessing the solid-state characteristics of API and functional excipients in complex dosage forms like osmotic tablets.

Development and Evaluation of Elementary Osmotic Pump Tablet of Tizanidine Hydrochloride

Aim The objective of present research work was to develop a sustained release osmotic tablet of Tizanidine HCl using suitable osmogens.Methodology Tizanidine HCl containing elementary osmotic tablets were prepared using a wet granulation process. Initially dried granules were screened for various pre compression evaluation parameters. Further dried granules were punched using 8 mm die cavity in a tablet punching machine. Thus developed tablets were evaluated for post compression parameters like tablet hardness thickness weight variation friability dissolution studies stability studies and scanning electron microscopy. Prior to dissolution studies an orifice was drilled on surface of tablet and the size of orifice was determined using SEM analysis.Results The pre compression evaluation for all the formulations had shown good results which in turn confirm excellent flow properties of granules. All formulations exhibited a weight gain of roughly 5-7. Dissolution studies confirm that the drug release pattern was controlled up to 24 hours formulation F9 had the maximum drug release around 97.27 at the end of 24 hours. The drug release was impacted by the amount of added osmogen microcrystalline cellulose and lactose concentrations. SEM studies were carried out to find the membrane surface diameter of the orifice and it was found to be 0.3 mm and revealed that the coat was intact devoid of pores after the dissolution. Kinetic study confirmed that all the formulations followed Zero order kinetics. Optimized formulation F9 was stable at room temperature and elevated temperature upto 30 days.Conclusion Developed Tizanidine HCl elementary osmotic pump tablets showed prolonged release of drug and found reproducible results for all the in vitro evaluation parameters.

Developing a Biorelevant Dissolution Method for an Extrudable Core System (ECS) Osmotic Tablet.

The objective of this work is to develop a biorelevant dissolution method to support the clinical study for In Vitro In Vivo Correlation (IVIVC) of the first commercially approved single-layer extrudable core system (ECS) osmotic tablet - the 11mg tofacitinib modified-release tablet. The dissolution conditions were selected through analysis of experimental work including several designed experiments (DoE). The Apparatus 2 (paddles) was selected over the Apparatus 1 (baskets) to minimize the dissolution test variability. The paddle speed was kept at 50rpm to be conservative and because higher paddle speed did not offer statistically significant improvement in dissolution test variability. The buffer of 50mM potassium phosphate at pH 6.8 was selected over other buffers at lower or acid pH as the in vivo drug release is expected to occur in the small intestinal region, where the pH is approximately neutral. Finally, the statistically designed experiments proved that use of the Japanese basket sinkers was effective in reducing dissolution variability and eliminating the artificial shift in dissolution profile caused by final pink color-coated tablets sticking to the dissolution vessel. Discriminatory power of the method was verified and the method was validated per ICH and FDA guidelines. Since a Level A IVIVC is established from the analysis of the results of both in vivo clinical study and in vitro dissolution testing, the method is proven to be biorelevant. It also serves a suitable quality control dissolution method.

Formulation and Evaluation of Enteric Coated Elementary Osmotic Tablets of Aceclofenac

This study aimed to develop a controlled drug delivery device for aceclofenac, a non-steroidal anti-inflammatory drug. Therefore, the agent was projected to develop an osmotic pump with enteric coating. The strength of the semipermeable membrane was improved by optimizing the formulation of the device, which can control the drug release over a prolonged period of time. The formulations were designed and optimized by using the statistical design of experiment followed by 32 factorial design to discover the best formulation. Several evaluation tests were performed to assess the physical parameters of the formulations. The percentage drug release of the formulations was observed for up to 9 h. The model 3D graph analysis indicated that as an osmogen, a higher percentage of potassium chloride was utilized more effectively than mannitol for the rapid dissolution of osmotic tablets. The optimized formulation can release 88.60±0.02% up to 9 h. The accelerated stability study confirmed that the optimized formulation was stable. The formulated osmotic tablets of aceclofenac were therapeutically safe and effective and did not release any drug content in the simulated gastric medium for a predetermined time.

FORMULATION AND EVALUATION OF DUAL-LAYERED OSMOTIC PUMP CONTROLLED-RELEASE TABLETS OF CEFIXIME

Background: This study aims to formulate, optimize and evaluate the osmotic tablet of cefixime. It improves the site specification and provides the controlled release of drug once – a – day through this drug delivery system. Cefixime assumes a significant part in dissolvability restricts other than dissolvable sort. It might increase the bioavailability of drugs by the preparation of the osmotic tablet. Method: The forming core tablet does a formulation of Controlled Porosity Osmotic Tablets (CP1 – CP9) using an ingredient like sodium chloride, PVP K30, Microcrystalline cellulose various ratios. The coating of the core tablet is done by Cellulose Acetate, PEG 400, with statistical ratios. Result: On depending upon the various evaluation parameters like hardness, diameter, friability, weight variation, content uniformity, In vitro release, CP9 formulation gave better consequence. The percentage of drug release is >95%. The optimized CP9 batch showed a maximum correlation of 0.992 with a zero-order drug release kinetic model. Conclusion: A controlled release formulation of cefixime based on osmotic technology, were developed. The release from the developed formulation was independent of pH and agitational intensity of the release media; the formulation fitted well into zero-order kinetics, indicating the release to be drug load independent. Drug release was directly proportional to the initial pore level but inversely related to the membrane weight. The release was inversely associated with the release media's osmotic pressure, confirming osmotic pumping as the central mechanism of release.

Quality by Design (QbD)-Based Numerical and Graphical Optimization Technique for the Development of Osmotic Pump Controlled-Release Metoclopramide HCl Tablets.

PurposeTo develop the osmotically controlled-release gastroprokinetic metoclopramide HCl tablets, using quality by design (QbD)-numerical and graphical optimization technique for the treatment of gastroparesis and prophylaxis of delayed nausea and vomiting induced by low-high emetogenic chemotherapy.MethodsFormulations were designed by central composite design using Design Expert version 11.0.0, with osmogen concentration (X1), orifice size (X2), and tablet weight gain after coating (X3) as input and in-vitro drug release at 1hr. (Y1), 6 hrs. (Y2), and 12 hrs. (Y3), and the regression coefficient of drug release data fitted to zero-order, RSQ zero (Y4) as output variables. Core tablets prepared by direct compression were coated with Opadry® CA. The experimental design was validated by the polynomial equation. A correlation between predicted and observed values was evaluated by random checkpoint analysis. The optimized formulations were characterized for drug release, pH effect, osmolarity, agitation intensity, surface morphology, and stability study, and were subjected to accelerated studies according to ICH guidelines.ResultsThe interaction charts and response surface plots deduced a significant simultaneous effect of X variables on in vitro drug release and RSQ zero. The numerical optimization model predicted >90% drug release with X1 (13.30%), X2 (0.6 mm), and X3 (7.96%). Random checkpoint analysis showed a good correlation between predicted and observed values. The optimized formulation followed zero-order kinetics (r2=0.9703) drug release. Shelf life calculated was 2.8 years as per ICH guidelines.ConclusionThe QbD-based approach was found successful in developing controlled release osmotic tablets of metoclopramide HCl, for reducing the dosage frequency, better emetic control, and improve patient compliance.

Evaluation of the Effect of Dissolution Conditions on the Release Profiles of Felodipine from the Extended Release Push-Pull Osmotic Tablets

The bilayered push–pull osmotic tablets of 5 mg felodipine were prepared by the double compression method, then the core tablets were coated with cellulose acetate as a semipermeable membrane. One releasing orifice was drilled by laser on the drug side of tablets. The osmotic tablets of felodipine containing low molecular weight PEO (200.000) as the primary component in the drug layer, high molecular weight PEO (5.000.000) as a swelling agent in the push layer and natri chloride as osmotic agent in both drug and push layers which were semi-permeable membrane coated with a weight gain of 8.5 % and the drilled release orifice of 0.8 mm. The influence of dissolution conditions on the release profiles of felodipine from the extended release push-pull osmotic tablets was studied. Dissolution studies of the osmotic tablets of felodipine were carried out in dissolution media with different media pH, stirring speeds or osmotic pressures. The results of the study showed that the drug release profile was similar in dissolution media containing surfactant mimics the in vivo state with varying pH and stirring speeds. However, felodipine released from the osmotic tablets was inversely proportional to the osmotic pressure of the dissolution medium. Therefore, the drug release rate from the osmotic tablets was independent of media pH and stirring speeds, but dependent on the osmotic pressure of the dissolution medium.
 Keywords
 Felodipine, push - pull osmotic pump, pH, stirring speeds, osmotic pressure.
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