Fed State Simulated Gastric Fluid Research Articles

Crushing the Contents of Valbenazine Capsules for Potential Addition to Soft Foods or Administration via Gastrostomy Tube

PurposeOne-capsule, once-daily valbenazine is approved for tardive dyskinesia and under evaluation for chorea associated with Huntington's disease, conditions in which patients often experience dysphagia. In vitro studies were conducted to assess the suitability of crushing the contents of valbenazine capsules (40 and 80 mg) for mixing with soft foods or liquids or administration via a gastrostomy tube (G-tube). MethodsIn study 1, the dissolution of whole valbenazine capsules and crushed capsule contents were measured serially for 1 hour. In study 2, valbenazine recovery was evaluated after crushed contents were mixed with soft foods, buffer solutions (pH range, 1.2–6.8), and fed-state simulated gastric fluid. In study 3, valbenazine recovery was evaluated after crushed contents were dispersed in water and delivered via a G-tube. In studies 2 and 3, acceptable valbenazine recovery was 90% to 110%. FindingsStudy 1 indicated rapid and complete drug release for whole valbenazine capsules and crushed capsule contents, with similar release at 10 minutes (whole, 94%–99%; crushed, 98%–100%) and 60 minutes (whole, 101%–103%; crushed, 101%–102%). Study 2 found acceptable valbenazine recovery within 2 hours of adding crushed capsule contents to tested foods, buffers, or fed-state simulated gastric fluid (recovery, 92%–102%). Study 3 found acceptable valbenazine recovery when crushed contents were added to cold or hot water and delivered via G-tube, with a water cup rinse to capture residual contents (recovery, 91%–97%). ImplicationsThese studies indicate the potential viability of valbenazine formulation(s) that can be added to soft foods or liquids or delivered via G-tube. Such formulations will be important for individuals who require treatment with a vesicular monoamine transporter 2 inhibitor but cannot swallow whole pills.

Solid lipid nanoparticles cyclodextrin-decorated incorporated into gellan gum-based dry floating in situ delivery systems for controlled release of bioactive compounds of safflower (Carthamus tinctorius. L): A proof of concept study in biorelevant media

Safflower (Carthamus tinctorius L.) has been explored as a source of natural antioxidant. However, quercetin 7-O-beta-D-glucopyranoside and luteolin 7-O-beta-D-glucopyranoside, as its bioactive compounds, possessed poor aqueous solubility, limiting its efficacy. Here, we developed solid lipid nanoparticles (SLNs) decorated with hydroxypropyl beta-cyclodextrin (HPβCD) incorporated into dry floating gel in situ systems to control the release of both compounds. Using Geleol® as a lipid matrix, SLNs were <200 nm in size with >80 % of encapsulation efficiency. Importantly, following the decoration using HPβCD, the stability of SLNs in gastric environment was significantly improved. Furthermore, the solubility of both compounds was also enhanced. The incorporation of SLNs into gellan gum-based floating gel in situ provided desired flow and floating properties, with <30 s gelation time. The floating gel in situ system could control the release of bioactive compounds in FaSSGF (Fasted-State Simulated Gastric Fluid). Furthermore, to assess the effect of food intake on release behavior, we found that the formulation could show a sustained release pattern in FeSSGF (Fed-State Simulated Gastric Fluid) for 24 h after being released in FaSGGF for 2 h. This indicated that this combination approach could be a promising oral delivery for bioactive compounds in safflower.

Survival of human coronavirus 229E at different temperatures on various food-contact surfaces and food and under simulated digestive conditions

The COVID-19 pandemic caused by SARS-CoV-2 has had a major impact on human health and the global economy. Various transmission possibilities of SARS-CoV-2 have been proposed, such as the surface of food in the cold chain and food packaging, as well as the fecal-oral route, although person-to-person contact via droplets and aerosols has been confirmed as the main route of transmission. This study evaluated the survivability of HCoV-229E, a SARS-CoV-2 surrogate, in suspension, on food-contact surfaces and on food at various temperatures, and in simulated digestive fluids by TCID50 assay. In suspension, HCoV-229E survived after 5 days at 20 °C with a 3.69 log reduction, after 28 days at 4 °C with a 3.07 log reduction, and after 12 weeks at –20 °C with a 1.18 log reduction. On food-contact surfaces, HCoV-229E was not detected on day 3 on stainless steel (SS), plastic (LDPE), and silicone rubber (SR) at 20 °C with a 3.28, 3.24 and 3.28 log reduction, respectively, and survived after 28 days on SS and LDPE at 4 °C with a 3.13 and 2.88 log reduction, respectively, and survived after 12 weeks on SS, LDPE, and SR at –20 °C with a 1.92, 1.32 and 1.99 log reduction, respectively. On food, HCoV-229E was not detected on day 3 on lettuce and day 4 on chicken breast and salmon at 20 °C with a 3.61, 3.26 and 3.08 log reduction, respectively, and on day 14 on lettuce and day 21 on chicken breast and salmon at 4 °C with a 3.88, 3.44 and 3.56 log reduction, respectively. The virus remained viable for 12 weeks in all foods at –20 °C with 2–2.47 log reduction. In addition, in simulated digestive fluid experiments, HCoV-229E was relatively resistant in simulated salivary fluid (SSF; pH 7, 5), fed state simulated gastric fluid (FeSSGF; pH 3, 5, 7), and fasted state simulated intestinal fluid (FaSSIF; pH 7). However, the virus was less tolerant in fasted state simulated gastric fluid (FaSSGF; pH 1.6) and fed state simulated intestinal fluid (FeSSIF; pH 5). Therefore, this study suggested that HCoV-229E remained infectious on various food-contact surfaces and foods; in particular, it survived longer at lower temperatures and survived depending on the pH of the simulated digestive fluid.

A novel in vitro approach to investigate the effect of food intake on release profile of valsartan in solid dispersion-floating gel in-situ delivery system

Valsartan (VAL) is a BCS class II drug with low solubility and high permeability and, thus, its formulations often encounter low bioavailability problems. Its low bioavailability can be improved through enhanced formulation, such as incorporating it into a solid dispersion system (SD). The absorption can be further enhanced through gastroretentive systems. Herein, we developed a novel combination delivery approach consisting of floating in-situ gel and SD. VAL was incorporated with polymer carrier PVP and PEG 6000 and its solubility was then evaluated. The study found that VAL-SD containing PVP K-30 as the carrier with drug:PVP K-30 ratio of 1:3 shown highest solubility in different media. Moreover, DSC and XRD evaluations exhibited the change of VAL from crystal to amorphous following SD formulation. The SD was then formulated into floating in-situ gel preparations using sodium alginate as gel forming compound and HPMC as the controlled release matrix. The prepared VAL-SD floating in-situ gels were evaluated for their physical properties and drug release profile. The results showed that all physical evaluation of the floating in-situ gel formula possessed desirable physical properties and the use of HPMC in floating in-situ gel was able to sustain the in vitro release of VAL for 24 h in biorelevant media. Importantly, the effect of food intake on VAL release was also investigated, for the first time, showing that the VAL release could be controlled in FaSSGF (Fasted-State Simulated Gastric Fluid) in 2 h and FeSSGF (Fed-State Simulated Gastric Fluid) onwards. Thus, in can be hypothesized that the food intake did not affect the VAL release after 2 h in an empty gastric environment. Leading on from these results, in vivo studies in an animal model should be carried out to further assess the potency of this system.

Biorelevant dissolution models to assess precipitation of weak base drug

The impact of precipitation can affect the amount of drug absorbed, thereby affecting the amount of drug in the systemic body. The precipitation process is preceded by a supersaturation phase, caused by decreased drug solubility in the gastrointestinal tract. This precipitation occurs for weak base drugs with low solubility. When the drug entering the small intestine, the solubility of weak base drugs decrease, then occurs supersaturation, which leads to precipitation, so that drug precipitation is one of a challenge for the pharmaceutical industry in drug development. Precipitation testing of water-soluble weak base drugs can be carried out by the pH shift method to describe the gastrointestinal pH gradient from gastric to small intestine. This pH change can cause supersaturation and then trigger precipitation, especially for weak base drugs. The methods that can used to assess precipitation drug is modification of the USP dissolution which are two compartment and multi compartment model. The choice of dissolution medium play an important role in the test results. The use of bio relevant medium can produce closer in vitro and in vivo correlations than the use of buffers. Generally, the medium used to simulate the weakly condition in the small intestine is FaSSIF (Fasted State Simulated Intestinal Fluid) or FeSSIF (Fed State Stimulate Intestinal Fluid) medium. The medium used to simulate the acidic condition in the stomach is FaSSGF (Fasted state simulated gastric fluid) or FeSSGF (Fed state simulated gastric fluid) medium.

Similarity of dissolution profiles from biorelevant media: Assessment of interday repeatability, interanalyst repeatability, and interlaboratory reproducibility using ibuprofen and ketoconazole tablets

Biorelevant media are increasingly being employed as dissolution media in drug development, including in smaller volumes than 900ml and under non-sink conditions. The objectives were to assess interday repeatability, interanalyst repeatability, and interlaboratory reproducibility of dissolution profiles from biorelevant media, as well as to assess the impacts of biorelevant media production method and biorelevant medium volume on dissolution profiles. Ibuprofen and ketoconazole tablets were subjected to dissolution testing in 500ml, 300ml, and 40ml of fasted state simulated gastric fluid (FaSSGF), fed state simulated gastric fluid (FeSSGF), fasted state simulated intestinal fluid version 2 (FaSSIF-V2), and fed state simulated intestinal fluid version 2 (FeSSIF-V2). f2 was used to assess repeatability and reproducibility of dissolution profiles. Results indicate favorable interday repeatability (83 of 88 comparisons were similar), favorable interanalyst repeatability (19 of 21 comparisons were similar), and favorable interlaboratory reproducibility (10 of 14 comparisons were similar) of dissolution profiles from biorelevant media, with commercial media showing greater interlaboratory reproducibility than ‘from scratch’ media. However, biorelevant medium production had low impact on profiles when one analyst conducted all medium preparations and study procedures at one location. Additionally, biorelevant media detected differences when products were not similar. Overall, biorelevant media showed favorable repeatability and reproducibility performance.

Development and Validation of Sample Preparation and an HPLC Analytical Method for Dissolution Testing in Fed-State Simulated Gastric Fluid-Illustrating Its Application for Ibuprofen and Ketoconazole Immediate Release Tablets.

Dissolution testing and solubility determinations in different biorelevant media have gained considerable interest in the pharmaceutical industry from early-stage development of new products to forecasting bioequivalence. Among all biorelevant fluids, the preparation of fed-state simulated gastric fluid (FeSSGF) and handling of samples from dissolution/solubility testing in FeSSGF is considered to be relatively challenging. Challenges include maintaining the stability of FeSSGF medium upon sampling, filtration, and mitigating analytical interference of excipients and milk components. To overcome these challenges, standard and uniform working practices are required that are not only helpful in preparation of stable FeSSGF but also serve as a harmonizing guide for the collection of dissolution/solubility samples and their subsequent processing (i.e., handling and assay). The optimization of sample preparation methodology is crucial to reduce method-related variance by ensuring specificity, robustness, and reproducibility with acceptable recovery of the analytes. The sample preparation methodology includes a combination of techniques including filtration, solvent treatment, and centrifugation to remove the interfering media-related components and excipients from the analyte. The analytes of interest were chromatographically separated from the interfering analytes to quantify the drug concentration using the new high-performance liquid chromatography methods with ultraviolet detection. The methods developed allow rapid sample preparation, acceptable specificity, reproducible recoveries (greater than 95% of label claim), and quantification of study drugs (ibuprofen and ketoconazole). The sample preparation technique and method considerations provided here for ibuprofen and ketoconazole can serve as a starting point for solubility and dissolution testing of other small molecules in FeSSGF.

Robustness of Controlled Release Tablets Based on a Cross-linked Pregelatinized Potato Starch Matrix.

The aim of this study was to evaluate the potential of a cross-linked pregelatinized potato starch (PREGEFLO® PI10) as matrix former for controlled release tablets. Different types of tablets loaded with diprophylline, diltiazem HCl or theophylline were prepared by direct compression of binary drug/polymer blends. The drug content was varied from 20 to 50%. Two hydroxypropyl methylcellulose grades (HPMC K100LV and K100M) were studied as alternative matrix formers. Drug release was measured in a variety of release media using different types of experimental set-ups. This includes 0.1N HCl, phosphate buffer pH6.8 and water, optionally containing different amounts of NaCl, sucrose, ethanol or pancreatin, fasted state simulated gastric fluid, fed state simulated gastric fluid, fasted state simulated intestinal fluid, fed state simulated intestinal fluid as well as media simulating the conditions in the colon of healthy subjects and patients suffering from Crohn's disease. The USP apparatuses I/II/III were used under a range of operating conditions and optionally coupled with the simulation of additional mechanical stress. Importantly, the drug release kinetics was not substantially affected by the investigated environmental conditions from tablets based on the cross-linked pregelatinized potato starch, similar to HPMC tablets. However, in contrast to the latter, the starch-based tablets roughly kept their shape upon exposure to the release media (they "only" increased in size) during the observation period, and the water penetration into the systems was much less pronounced. Thus, the investigated cross-linked pregelatinized potato starch offers an interesting potential as matrix former in controlled release tablets.

Investigation of drug partition kinetics to fat in simulated fed state gastric conditions based on drug properties.

The presence of fat in the gastric environment can affect the pharmacokinetic behaviour of drugs with mechanisms which have not been yet fully understood. The objective of the current study was to assess the drug partition to the lipid part of the fed gastric content under different emulsification conditions, using in vitro discriminating setups. The model drugs used in the study were selected on the basis of different physicochemical properties (lipophilicity, ionization, molecular weight and aqueous solubility) and different food effect observed in in vivo human studies. Fed State Simulated Gastric Fluid prepared with skimmed milk (FeSSGFsk) and anhydrous milk fat were used as surrogates for the aqueous and fat portions of the fed gastric environment respectively. An optimized biphasic model was developed so as to predict the differences in partition rate constants to fat, for model drugs of a wide range of the properties mentioned above. The experimental data and the use of statistical analysis revealed that molecular weight, molecular weight and log D pH 5 interaction and negative food effect act as negative factors to the rate constants of fat partition, while absence of food effect and logD pH 5 interaction with aqueous solubility affect the rate constants of partition to fat favourably.

Impact of presence of excipients in drug analysis in fed-state gastric biorelevant media

In this study, the influence of the presence of excipients in sample preparation and clean-up steps required prior to drug analysis in milk-based media which simulate the in vivo properties of the fed state stomach was investigated. 15 excipients, normally present in solid dosage forms of five APIs tested (atenolol, paracetamol, furosemide, nifedipine and propafenone hydrochloride) were mixed (one at a time) with the active pharmaceutical ingredient of interest either via vortexing, co-grinding or shaking of the physical mixture and dissolved in Fed State Simulated Gastric Fluid (FeSSGF). The objective of the study was the assessment of the extraction efficiency of three protein precipitation protocols (using MeOH, ΑCN and 10% w/v TCA), typically used in drug analysis, in milk-based biorelevant media in the presence of the excipients. The mixing technique, fat content of the medium and excipient and solvent effects were investigated. The efficiency of three different protein precipitation reagents in drug extraction when dissolved as API:excipient mixtures in the fed-state medium was compared against the equivalent drug amount recovered in the absence of the excipient in FeSSGF. Most excipients had a significant negative effect (p < 0.05) on drug recovery in the milk-based medium as indicated by the multiple linear regression (MLR) analysis performed. For magnesium stearate and HPMC, the % recovery values were the lowest in four out of the five drugs studied, with a range of 10–100% depending on the API, mixing technique and protein precipitation protocol selected. The negative excipient-dependent effect was more profound in nifedipine and propafenone hydrochloride, the most lipophilic compounds of the study. Acetonitrile was the most effective extraction reagent for most drugs in the presence of excipients, followed by methanol and 10% w/v trichloroacetic acid. Data analysis also revealed a dependence of the extraction method efficiency on the medium lipid content. Application of the above extraction protocols in commercially available formulations highlighted the need for assessment of the effect of excipients in extraction efficiency, before transferring the method directly to dissolution studies of formulations in milk-based fed gastric media. In conclusion, the presence of excipients and the selection of protein precipitation protocol are parameters which can affect significantly the efficiency of protein precipitation when FeSSGF is used as dissolution medium and need to be taken into consideration when developing a quantitative method based on the above sample clean-up technique.

Strategic drug analysis in fed-state gastric biorelevant media based on drug physicochemical properties

Milk-based media such as the Fed State Simulated Gastric Fluid (FeSSGF) are commonly used in order to simulate the in vivo properties of the fed state stomach. Due to the lack of a specific guideline for standardised sample clean-up in these media, the aim of the current study was to develop an optimum protocol for the extraction and quantification of drugs from the fed state gastric medium based on the APIs’ physicochemical properties (lipophilicity, ionisation, aqueous solubility and protein binding). Two different extraction techniques, protein precipitation (PP) and solid phase extraction (SPE) were assessed. A pilot study in six model drugs was performed, with tests using seven different protein precipitation reagents at four different medium:reagent ratios and two drug concentrations as well as different solid phase extraction cartridges and elution protocols. % recovery was analysed using partial least squares (PLS) regression so as to determine the physicochemical parameters affecting the drug percentage recovered. For protein precipitation protocols, drug concentration, selection of protein precipitation reagent and ratio added to the medium significantly affected drug % recovery from FeSSGF (p < 0.05). The same applied for the selection of elution solvent and cartridge type for solid phase extraction. Optimum protocols using MeOH, ΑCN and 10% w/v TCA at a 1:2 FeSSGF:reagent ratio were effective to a larger group of drugs of a wide range of lipophilicity and ionisation, with ΑCN being the most effective in the whole range of log P values (−0.56 to 8.81). Solid phase extraction was proven to be effective for compounds of poor to moderate lipophilicity (log P < 4), with extremely hydrophobic compounds demonstrating lower % recovery values (down to 10% recovery). PLS demonstrated that only for 10% w/v TCA (protein precipitation) and HLB (solid phase extraction) can the effect of key drug physicochemical properties on the final amount of drug recovered be accurately predicted.

Avoidance of food effect on oral absorption profile of itraconazole by self-micellizing solid dispersion approach

The present study was aimed to avoid pharmacokinetic transitions of itraconazole (ITZ) evoked by high-fat meal intake by employing a self-micellizing solid dispersion (SMSD) approach. The dissolution behavior of SMSD/ITZ was assessed in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). To evaluate the food effect on the oral absorption profile of ITZ, a pharmacokinetic study was conducted on orally-dosed ITZ samples in fasted and high-fat meal-fed rats. Crystalline ITZ showed a 9.0-fold higher dissolution amount of ITZ in fed-state SGF (FeSSGF) than in fasted-state SGF (FaSSGF), whereas there was no significant difference in the dissolution amount of ITZ in SMSD/ITZ between FeSSGF and FaSSGF. In fed- and fasted-state SIF, SMSD/ITZ exhibited reduced variation of ITZ dissolution, possibly leading to suppression of the food effect on the dissolution behavior of ITZ. After the oral administration of crystalline ITZ to high-fat meal-fed rats, the oral bioavailability of ITZ was 14-fold higher than that in fasted rats. In contrast, orally-dosed SMSD/ITZ in fed rats exhibited limited transition of pharmacokinetic behavior regardless of food intake due to the improvement in the dissolution behavior of ITZ even under fasted conditions. SMSD technology could be an efficacious dosage option for the consistent oral absorption and clinical outcomes of ITZ.

Stability behaviour of antiretroviral drugs and their combinations. 4: Characterization of degradation products of tenofovir alafenamide fumarate and comparison of its degradation and stability behaviour with tenofovir disoproxil fumarate

In this study, stress degradation behaviour of tenofovir alafenamide fumarate (TAF), a novel prodrug of tenofovir, was investigated and compared with currently used prodrug congener, tenofovir disoproxil fumarate (TDF), whose intrinsic stability was reported by us earlier [14]. Also, pH stability and gastrointestinal stability studies were conducted on both the drugs. High performance liquid chromatography (HPLC) analysis of stressed samples of TAF revealed formation of six degradation products (DPs) against twelve characterized earlier in the case of TDF (RSC Adv. 5(2015) 96117-96129). Like TDF, characterization of DPs of TAF was done by using sophisticated hyphenated liquid chromatography-high resolution mass spectrometry (LC-HRMS) and multistage mass spectrometry (MSn) tools. pH-stability studies between pH 1.2–10 revealed greater stability of TAF, except in acidic conditions, where TAF was degraded extensively. Investigation of gastrointestinal stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and fed state simulated gastric fluid (FeSSGF) suggested that TAF must be administered in fed state, as the drug was practically stable in FeSSGF as compared to extensive loss at acidic pH and in SGF.

Development of an in Vitro System to Simulate the Adsorption of Self-Emulsifying Tea (Camellia oleifera) Seed Oil.

In this study, tea (Camellia oleifera) seed oil was formulated into self-emulsifying oil formulations (SEOF) to enhance the aqueous dispersibility and intestinal retention to achieve higher bioavailability. Self-emulsifying tea seed oils were developed by using different concentrations of lecithin in combination with surfactant blends (Span®80 and Tween®80). The lecithin/surfactant systems were able to provide clear and stable liquid formulations. The SEOF were investigated for physicochemical properties including appearance, emulsion droplets size, PDI and zeta potential. The chemical compositions of tea seed oil and SEOF were compared using GC-MS techniques. In addition, the oil adsorption measurement on artificial membranes was performed using a Franz cell apparatus and colorimetric analysis. The microscopic structure of membranes was observed with scanning electron microscopy (SEM). After aqueous dilution with fed-state simulated gastric fluid (FeSSGF), the droplet size of all SEOF was close to 200 nm with low PDI values and the zeta potential was negative. GC-MS chromatograms revealed that the chemical compositions of SEOF were not significantly different from that of the original tea seed oil. The morphological study showed that only the SEOF could form film layers. The oil droplets were extracted both from membrane treated with tea seed oil and the SEOF in order to evaluate the chemical compositions by GC-MS.

Ultra rapidly dissolving repaglinide nanosized crystals prepared via bottom-up and top-down approach: influence of food on pharmacokinetics behavior.

The present work was undertaken with the objectives of improving the dissolution velocity, related oral bioavailability, and minimizing the fasted/fed state variability of repaglinide, a poorly water-soluble anti-diabetic active by exploring the principles of nanotechnology. Nanocrystal formulations were prepared by both top-down and bottom-up approaches. These approaches were compared in light of their ability to provide the formulation stability in terms of particle size. Soluplus® was used as a stabilizer and Kolliphor™ E-TPGS was used as an oral absorption enhancer. In vitro dissolution profiles were investigated in distilled water, fasted and fed state simulated gastric fluid, and compared with the pure repaglinide. In vivo pharmacokinetics was performed in both the fasted and fed state using Wistar rats. Oral hypoglycemic activity was also assessed in streptozotocin-induced diabetic rats. Nanocrystals TD-A and TD-B showed 19.86 and 25.67-fold increase in saturation solubility, respectively, when compared with pure repaglinide. Almost 10 (TD-A) and 15 (TD-B)-fold enhancement in the oral bioavailability of nanocrystals was observed regardless of the fasted/fed state compared to pure repaglinide. Nanocrystal formulations also demonstrated significant (p < 0.001) hypoglycemic activity with faster onset (less than 30 min) and prolonged duration (up to 8 h) compared to pure repaglinide (after 60 min; up to 4 h, respectively).

ChemInform Abstract: Simulating the Postprandial Stomach: Biorelevant Test Methods for the Estimation of Intragastric Drug Dissolution

AbstractReview: 73 refs.

Simulating the Postprandial Stomach: Biorelevant Test Methods for the Estimation of Intragastric Drug Dissolution

Intragastric drug release from solid oral dosage forms can be affected by altered physicochemical and mechanical conditions in the upper gastrointestinal (GI) tract. Food effects may lead to changes of one or more pharmacokinetic parameters and, hence, influence drug plasma levels. This can result in severe consequences such as adverse drug reactions or even therapy failure. This review highlights different examples of drug performance under fed conditions. Various reasons such as delayed gastric emptying and pH-dependent solubility of the API as well as intragastric location and movement profiles of solid dosage forms can account for changed drug dissolution. Over the past years, several biorelevant media (e.g., fed state simulated gastric fluid) have been developed with the aim to approach the physiological situation regarding parameters such as pH, buffer capacity, surface tension, and osmolality. It was shown in different in vitro experiments that all of these factors can have an impact on drug dissolution. Besides the application of complex media such as milk or nutritional drinks, the dynamic changes of the gastric content were depicted in recent studies. The capabilities, limitations, and applicability of newly established test setups for the biorelevant simulation of intragastric drug delivery behavior are discussed. Simple test devices (e.g., rotating beaker or dissolution stress test) are mainly used for the biopharmaceutical evaluation of certain problems such as the impact of pressure or shear forces. On the other hand, complex biorelevant test devices (e.g., TNO TIM-1, Dynamic Gastric Model) have recently been introduced aiming at the simulation of multiple parameters characteristic for the postprandial upper GI tract. The different test methods are reviewed with respect to the spectrum of the simulated physiological factors and the degree of complexity.

Simulated Biological Fluids with Possible Application in Dissolution Testing

This literature review is a compilation of the composition and, in most cases, the preparation instructions for simulated biological fluids that may be used as dissolution media in the evaluation of dissolution profiles and amount of drug released from pharmaceutical dosage forms. The use of simulated biological fluids can give a better understanding of the release mechanisms and possible in vivo behavior of a product and enhance the predictive capability of the dissolution testing. A summary of the major characteristics of the most used routes of administration that may affect dissolution and absorption of drug substances is presented. The routes and simulated biological fluids covered by this review are: • Parenteral: simulated body fluid and simulated synovial fluid. • Oral: fasted-state simulated gastric fluid, fed-state simulated gastric fluid, fasted-state simulated intestinal fluid, fed-state simulated intestinal fluid, simulated colonic fluid, fasted-state simulated colonic fluid, and fed-state simulated colonic fluid. • Buccal and sublingual: simulated saliva. • Pulmonary: simulated lung fluid. • Vaginal: simulated vaginal fluid and simulated semen. • Ophthalmic: simulated tears. Simulated sweat is also included. Some examples of how these simulated biological fluids are used to evaluate dosage forms are included in each route of administration. INTRODUCTION Until some decades ago, most of the conventional pharmaceutical dosage forms were essentially injections, oral formulations (solutions, suspensions, tablets, and capsules), topical creams, and ointments. With the progress of drug delivery technology, novel dosage forms have been developed to overcome the problems associated with conventional drug delivery. Research has been directed toward the use of alternatives to the parenteral route for drugs that cannot be delivered orally. Potential alternative portals of drug entry to the systemic circulation include buccal, sublingual, nasal, pulmonary, and vaginal routes, among others. These routes of administration are also used for the local delivery of drugs directly to the site of action, with consequent reduction in the dose needed to produce a pharmacological effect, eliminating problems related to first-pass metabolism and possibly minimizing systemic side effects (1). An important application of dissolution testing is the prediction of in vivo performance of pharmaceutical dosage forms. The media typically used for quality control dissolution testing do not represent all aspects of the physiological conditions of the most used routes of administration and do not allow correlation with in vivo data. Prediction of dosage form performance in the site where most of the absorption occurs requires adequate simulation of the in vivo conditions. This paper describes some characteristics of the parenteral, oral, buccal and sublingual, pulmonary, ophthalmic, and vaginal routes that are important to consider when developing simulated media. A compilation of the composition and preparation of several simulated biological fluids, including simulated sweat, with potential use as dissolution media is presented. PARENTERAL ROUTE The most used routes of injection are intramuscular, intravenous, and subcutaneous and are normally associated with short-term effects. Novel implant devices that can adequately control drug release and provide a prolonged duration of effect have been developed (1). To evaluate the in vitro drug release from these dosage forms, the dissolution medium should have ion concentrations almost equal to those of the human plasma. Table 1 describes the ionic composition of simulated body fluid (SBF) and human blood plasma. Simulated body fluid was developed initially to evaluate the surface structural changes of glass-ceramics used to manufacture artificial vertebrae, ileum, tooth roots (2), and bioactive material used to repair hard tissues such as artificial middle-ear bone and maxillofacial implants (3). This simulated body fluid was prepared using the reagents listed in Table 2. These reagents were added to 700 mL of water in the order given in Table 2, one by one, after each reagent was completely dissolved. The pH was adjusted to 7.4 with 1 M *Corresponding author. diss-18-03-03.indd 15 8/31/2011 3:22:15 PM dx.doi.org/10.14227/DT180311P15

Online monitoring of dissolution tests using dedicated potentiometric sensors in biorelevant media

The performance of the Ion-Selective Electrode (ISE) for in vitro dissolution testing using biorelevant media was evaluated in this study. In vitro dissolution was carried out using USP apparatus 2 (paddle method) with classical and with updated biorelevant media to simulate the pre- and postprandial states. The ISE was used as an analytical stand-alone system and in combination with a single-point HPLC–UV measurement. A modified method enabling the use of the ISE for very poorly soluble substances is also proposed. In terms of f 2-factor, the results acquired using the ISE for the drug diphenhydramine-HCl were found to be very similar to the results obtained by manual sampling followed by HPLC–UV analysis. In Fed State Simulated Gastric Fluid (FeSSGF), a medium containing 50% milk, the ISE is more practical since the need to separate proteins from the analyte prior to HPLC–UV analysis is eliminated. Further work will be needed to establish ISE methodology for Fed State Simulated Intestinal Fluid (FeSSIF) media. In summary, the ISE has promise as an analytical tool for research and development applications.

Impact of Gastric pH and Dietary Fiber on Calcium Availability of Various Calcium Salts

The objective of this study was to compare calcium release and ionization from commercialcalcium supplements and various salts of calcium with different solubilities. The impact of pH of testfluid and dietary fiber co-administered with calcium supplement on calcium availability was alsostudied. Compressed tablets of six different calcium salts were prepared by direct compression.Calcium release from tablets was tested in simulated gastric fluid without pepsin (SGF, pH 1.2) or fedstate simulated gastric fluid (FSSGF, pH 4.8), using USP dissolution apparatus. The ionized calciumconcentration in test fluid was determined by calcium ion selective electrode. The results demonstratedthat most of the formulations released calcium within 1 hour. Tablets made of higher solubilitycalcium salts demonstrated a faster calcium release. The calcium release from calcium hydrogenphosphate and calcium carbonate tablets in gastric fluid with higher pH showed a slower calciumrelease than in SGF. The dietary fiber co-administered with calcium supplement influenced thecalcium availability, especially in medium with higher pH. The results suggested that most of thecalcium salts could be used as calcium supplement. However, the use of calcium carbonate required anacidic environment in order to be dissolved in the gastrointestinal tract. Key Words: Calcium; Tablet; Gastric pH; Pectin; Dietary fiber