Rapid Structure Determination of Ranitidine Hydrochloride API in Two Crystal Forms Using Microcrystal Electron Diffraction.

The solid-state properties of drug candidates play a crucial role in their selection. Quality control of active pharmaceutical ingredients (APIs) based on their structural information involves ensuring a consistent crystal form and controlling water and residual solvent contents. However, traditional crystallographic techniques have limitations and require high-quality single crystals for structural analysis. Microcrystal electron diffraction (microED) overcomes these challenges by analyzing difficult-to-crystallize or small-quantity samples, making it valuable for efficient drug development. In this study, microED analysis was able to rapidly determine the configuration of two crystal forms (Forms 1, 2) of the API ranitidine hydrochloride. The structures obtained with microED are consistent with previous structures determined by X-ray diffraction, indicating microED is a useful tool for rapidly analyzing molecular structures in drug development and materials science research.

Advanced Solid-State NMR Analysis of Two Crystal Forms of Ranitidine Hydrochloride: Detection of 1H-14N Intra-/Intermolecular Correlations.

Understanding the characteristics of crystal polymorphism of active pharmaceutical ingredients and analyzing them with high sensitivity is important for quality of drug products, appropriate characterization strategies, and appropriate screening and selection processes. However, there are few methods to measure intra- and intermolecular correlations in crystals other than X-ray crystallography, for which it is sometimes difficult to obtain suitable single crystals. Recently, solid-state NMR has been recognized as a straightforward method for measuring molecular correlations. In this study, we selected ranitidine hydrochloride, which is known to exist in two forms, 1 and 2, as the model drug and investigated each form using solid-state NMR. In conducting the analysis, rotating the sample tube, which had a 1-mm inner diameter, increased the solid-state NMR resolution at 70 kHz. The 1H-14N dipolar-based heteronuclear multiple quantum coherence (D-HMQC) analysis revealed the intermolecular correlation of Form 1 between the N atom of the nitro group and a proton of the furan moiety, which were closer than those of the intramolecular correlation reported using single X-ray crystal analysis. Thus, 1H-14N D-HMQC analysis could be useful for characterizing intermolecular interaction in ranitidine hydrochloride crystals. In addition, we reassigned the 13C solid-state NMR signals of ranitidine hydrochloride according to the liquid-state and multiple solid-state NMR experiments.

N-Nitrosodimethylamine (NDMA) Formation from Ranitidine Impurities: Possible Root Causes of the Presence of NDMA in Ranitidine Hydrochloride.

N-Nitrosodimethylamine (NDMA) is a probable human carcinogen. This study investigated the root cause of the presence of NDMA in ranitidine hydrochloride. Forced thermal degradation studies of ranitidine hydrochloride and its inherent impurities (Imps. A, B, C, D, E, F, G, H, I, J, and K) listed in the European and United States Pharmacopeias revealed that in addition to ranitidine, Imps. A, C, D, E, H, and I produce NDMA at different rates in a solid or an oily liquid state. The rate of NDMA formation from amorphous Imps. A, C, and E was 100 times higher than that from crystalline ranitidine hydrochloride under forced degradation at 110 °C for 1 h. Surprisingly, crystalline Imp. H, bearing neither the N,N-dialkyl-2-nitroethene-1,1-diamine moiety nor a dimethylamino group, also generated NDMA in the solid state, while Imp. I, as an oily liquid, favorably produced NDMA at moderate temperatures (e.g., 50 °C). Therefore, strict control of the aforementioned specific impurities in ranitidine hydrochloride during manufacturing and storage allows appropriate control of NDMA in ranitidine and its pharmaceutical products. Understanding the pathways of the stability related NDMA formation enables improved control of the pharmaceuticals to mitigate this risk.

Preparation of Co-Processed Excipients for Controlled-Release of Drugs Assembled with Solid Lipid Nanoparticles and Direct Compression Materials.

The purpose of the study was to develop a novel, directly compressible, co-processed excipient capable of providing a controlled-release drug system for the pharmaceutical industry. A co-processed powder was formed by adsorption of solid lipid nanoparticles (SLN) as a controlled-release film onto a functional excipient, in this case, dicalcium phosphate dihydrate (DPD), for direct compression (Di-Tab®). The co-processed excipient has advantages: easy to implement; solvent-free; industrial scaling-up; good rheological and compressibility properties; and the capability to form an inert platform. Six different batches of Di-Tab®:SLN weight ratios were prepared (4:0.6, 3:0.6, 2:0.6, 1:0.6, 0.5:0.6, and 0.25:0.6). BCS class III ranitidine hydrochloride was selected as a drug model to evaluate the mixture's controlled-release capabilities. The co-processed excipients were characterized in terms of powder rheology and dissolution rate. The best Di-Tab®:SLN ratio proved to be 2:0.6, as it showed high functionality with good flow and compressibility properties (Carr Index = 16 ± 1, Hausner Index = 1.19 ± 0.04). This ratio could control release for up to 8 h, so it fits the ideal profile calculated based on biopharmaceutical data. The compressed systems obtained using this powder mixture behave as a matrix platform in which Fickian diffusion governs the release. The Higuchi model can explain their behavior.

Oil-entrapped ranitidine HCl beads heal peptic ulcers via local and systemic mechanisms.

OBJECTIVE: Oral gastroretentive system is one of the site-specific drug delivery system, which is designed to be retained in upper GIT for a prolonged time. Ranitidine hydrochloride (RHCl), which is used frequently in treatment of peptic ulcer, is a suitable candidate for gastroretentive delivery systems. Dependently, floating oil-entrapped alginate beads of RHCl were developed and evaluated as an approach to site-specific delivery avoiding colonic degradation and enhancing both bioavailability and the proposed local effect. METHODS: Different formulations of floating beads were suggested and randomized using 24 full factorial design. Optimized formulation was subjected for in vivo studies to measure the oral bioavailability and the healing effect of induced peptic ulcers. RESULTS: Beads size ranged from 1.32 to 2.3 mm. All beads revealed excellent floating capabilities. Optimum formulation (F12) has entrapment efficiency of 70%, drug loading of 7% and 71% RHCl released after 6 h. SEM of F12 shows a grossly spherical structure with presence of oil droplets distributed throughout structure. AUC obtained from F12 was nonsignificantly higher than that of a commercial tablet. Signs of ulcer healing appeared clearly with F12 through appearance of granulation tissue, collagen fibers and newly formed blood vessels. Healing rate and extent obtained with a commercial tablet were less than F12. Quantitative analysis confirmed histopathological findings. CONCLUSION: Floating oil-entrapped beads are a promising approach for RHCl delivery to remain in stomach for a longer time ensuring site-specific delivery and consequently, enhancing local healing effect of peptic ulcers.

Formulation and evaluation of floating tablet of H2-receptor antagonist.

CONTEXT: Conventional sustained dosage form of ranitidine hydrochloride (HCl) does not prevent frequent administration due to its degradation in colonic media and limited absorption in the upper part of GIT. OBJECTIVES: Ranitidine HCl floating tablet was formulated with sublimation method to overcome the stated problem. METHODS: Compatibility study for screening potential excipients was carried out using Fourier transform infrared spectroscopy (FT-IR) and differential scanning chromatography (DSC). Selected excipients were further evaluated for optimizing the formulation. Preliminary screening of binder, polymer and sublimating material was based on hardness and drug release, drug release with release kinetics and floating lag time with total floatation time, respectively. Selected excipients were subjected to 3(2) factorial design with polymer and sublimating material as independent factors. Matrix tablets were obtained by using 16/32" flat-faced beveled edges punches followed by sublimation. RESULTS: FT-IR and DSC indicated no significant incompatibility with selected excipients. Klucel-LF, POLYOX WSR N 60 K and l-menthol were selected as binder, polymer and sublimating material, respectively, for factorial design batches after preliminary screening. From the factorial design batches, optimum concentration to release the drug within 12 h was found to be 420 mg of POLYOX and 40 mg of l-menthol. Stability studies indicated the formulation as stable. CONCLUSION: Ranitidine HCl matrix floating tablets were formulated to release 90% of drug in stomach within 12 h. Hence, release of the drug could be sustained within narrow absorption site. Moreover, the dosage form was found to be floating within a fraction of second independent of the pH of media ensuring a robust formulation.

In Vitro and Biological Evaluation of Oral Fast-Disintegrating Films Containing Ranitidine HCl and Syloid® 244FP-Based Ternary Solid Dispersion of Flurbiprofen.

Flurbiprofen (FBP), a nonsteroidal anti-inflammatory drug (NSAID), is commonly used to treat the pain of rheumatoid arthritis, but in prolonged use it causes gastric irritation and ulcer. To avoid these adverse events of NSAIDs, the simultaneous administration of H2 receptor antagonists such as ranitidine hydrochloride (RHCl) is obligatory. Here, we developed composite oral fast-disintegrating films (ODFs) containing FBP along with RHCl to provide a gastroprotective effect as well as to enhance the solubility and bioavailability of FBP. The ternary solid dispersion (TSD) of FBP was fabricated with Syloid® 244FP and poloxamer® 188 using the solvent evaporation technique. The synthesized FBP-TSD (coded as TSD) was loaded alone (S1) and in combination with plain RHCl (S2) in the composite ODFs based on hydroxypropyl methyl cellulose E5 (HPMC E5). The synthesized composite ODFs were evaluated by in vitro (thickness, folding endurance, tensile strength, disintegration, SEM, FTIR, XRD and release study) and in vivo (analgesic, anti-inflammatory activity, pro-inflammatory cytokines and gastroprotective assay) studies. The in vitro characterization revealed that TSD preserved its integrity and was effectively loaded in S1 and S2 with optimal compatibility. The films were durable and flexible with a disintegration time ≈15 s. The release profile at pH 6.8 showed that the solid dispersion of FBP improved the drug solubility and release when compared with pure FBP. After in vitro studies, it was observed that the analgesic and anti-inflammatory activity of S2 was higher than that of pure FBP and other synthesized formulations (TSD and S1). Similarly, the level of cytokines (TNF-α and IL-6) was also markedly reduced by S2. Furthermore, a gastroprotective assay confirmed that S2 has a higher safety profile in comparison to pure FBP and other synthesized formulations (TSD and S1). Thus, composite ODF (S2) can effectively enhance the FBP solubility and its therapeutic efficacy, along with its gastroprotective effect.

In Vitro and In Vivo Evaluation of Composite Oral Fast Disintegrating Film: An Innovative Strategy for the Codelivery of Ranitidine HCl and Flurbiprofen.

Here, we evaluate the feasibility of co-loading plain ranitidine hydrochloride (RHCl) and microencapsulated flurbiprofen (FBP) in a Lycoat® RS780-based oral fast disintegrating film (ODF). These films were developed by the solvent casting method to minimize the adverse effects of FBP and reduce the dosage form burden on patients. Optimized FBP microparticles (M3) with an average size of 21.2 ± 9.2 µm were loaded alone (F1) and in combination with plain RHCl (F2) in the composite ODF. All films were evaluated physicomechanically and physicochemically. These films were resilient, flexible, and disintegrated within thirty seconds. SEM images showed intact FBP microparticles in both formulations and, moreover, did not observe an interaction between the drug and film components. Microencapsulated FBP was released in a controlled manner over 48 h from the proposed formulations, while RHCl was released within 5 min from F2. After in vitro evaluation, formulations were also tested for in vivo anti-inflammatory activity, cytokine (TNF-α and IL-6) levels, and gastroprotective effects in rats. The anti-inflammatory activity and gastroprotective effect of F2 were markedly higher than pure FBP and other synthesized formulations (M3 and F1). The average score of gastric lesions was in the order of pure FBP (15.5 ± 1.32) > M3 (8 ± 2) > F1 (1 ± 0.5) > F2 (0.5 ± 0) > control (0). Additionally, F2 showed a sustained anti-inflammatory effect up to 10 h in the rat paw edema model. Furthermore, F2 also markedly reduced TNF-α and IL-6 levels. Conclusively, the Lycoat® RS780-based composite film could be a promising carrier for the co-loading of microencapsulated FBP with RHCl. In the future, an optimized formulation (F2) could be capable of countering the issues related to multiple drug administration in geriatric patients and evading the gastric irritation associated with FBP.

Ultrasensitive Functionalized Polymeric-Nanometal Oxide Sensors for Potentiometric Determination of Ranitidine Hydrochloride.

Two metal oxide nanoparticles, magnesium oxide nanoparticles (MgONPs) and aluminum oxide nanoparticles (Al2O3NPs), were synthesized from green sources, Salvia officials and Cuminum cyminum seed extract, respectively. These nanoparticles were used for construction of potentiometric enhancement sensors employed for the estimation of ranitidine hydrochloride (RNT) in authentic powder and commercial products. The electroactive substance ranitidine-phosphotungstate (RNT-PT) was formed by combining RNT with phosphotungstic acid (PTA) in the presence of plasticizing material o-nitrophenyloctyl ether (o-NPOE). The outcomes showed that the enhanced MgO and Al2O3 nanosensors behaved linearly across the concentration ranges 1.0 × 10-9-1.0 × 10-2 and 1.0 × 10-10-1.0 × 10-2 mol L-1, respectively. However, the conventional sensor (RNT-PT) displayed a linearity over 1.0 × 10-6-1.0 × 10-2 mol L-1. Least square equations were calculated as EmV = (54.1 ± 0.5) log (RNT) + 762.33, EmV = (58.6 ± 0.2) log (RNT) + 696.48, and EmV = (52.2 ± 0.7) log (RNT) + 756.76 for enriched nanometal oxides modified and conventional sensors, respectively. The correlation coefficients of regression equations were 0.9997, 0.9995, and 0.9992 for the above suggested sensors, respectively. The recorded results showed excellent sensitivity and selectivity of the modified nanometal oxide sensors for the quantification of the analyzed drug in its authentic samples and commercial products.

3D printed gummies: Personalized drug dosage in a safe and appealing way.

Obtention of customized dosage forms is one of the main attractions of 3D printing in pharmaceuticals. In this sense, children are one of the groups within the population with a greater need for drug doses adapted to their requirements (age, weight, pathological state…), but most 3D printed oral dosages are solid forms and, therefore, not suitable for them. This work developed patient-tailored medicinal gummies, an alternative oral dosage form with eye-catching appearance and appropriate organoleptic characteristics. Four inks were formulated, characterised and 3D printed by means of syringe-based extrusion mechanism. Different tests were performed to ensure reproducibility of the process and validate work methodology for dosage unit fabrication applying basic manufacturing standards. Rheological test helped in evaluating inks printability. Visual characterization concluded that drugmies, apart from a high fidelity in the 3D model shape reproduction, had a bright and uniformly coloured appearance and a pleasant aroma, which made them highly appetising and attractive. The printed gummy oral dosages complied comfortably with the mass uniformity assay regardless of the formulated ink used or the 3D model selected for printing. Ranitidine hydrochloride individual contents were determined using uv-vis spectrophotometry, showing successful results both in dose accuracy, uniformity of drug content and dissolution.

Regional difference in intestinal drug absorption as a measure for the potential effect of P-glycoprotein efflux transporters.

OBJECTIVES: The aim of this research was to assess regional difference in the intestinal absorption of ranitidine HCl as an indicator for the potential effect of P-glycoprotein (P-gp) efflux transporters. METHODS: In situ rabbit intestinal perfusion was used to investigate absorption of ranitidine HCl, a substrate for P-gp efflux from duodenum, jejunum, ileum and colon. This was conducted both in the presence and absence of piperine as P-gp inhibitor. KEY FINDINGS: Ranitidine HCl was incompletely absorbed from rabbit intestine. The length normalized absorptive clearance (PeA/L) of ranitidine HCl was ranked as colon > duodenum > jejunum > ileum. This is the reverse order of the magnitude of P-gp expression. Coperfusion of piperine with ranitidine HCl significantly increased the PeA/L of ranitidine HCl from jejunum and ileum with no significant change on the absorption from duodenum and colon. This was confirmed by significant reduction in the length required for complete ranitidine HCl absorption from jejunum and ileum in presence piperine. CONCLUSIONS: The results indicate that P-gp transporters play a major role in determining regional difference in intestinal absorption of ranitidine HCl. Thus, the regional absorption of drugs may be taken as an indirect indication for the role of P-gp in intestinal absorption.

Involvement of histamine H1 and H2 receptor inverse agonists in receptor's crossregulation.

Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through histamine H1 and H2 receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H1 and H2 receptor crossdesensitization and cointernalization induced by its agonists have been previously described. In this study, we show how this crosstalk determines the response to histamine H1 and H2 receptor inverse agonists and how histamine H1 and H2 receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that histamine H1 and H2 receptor inverse agonists induce a crossregulation between both receptors. In this sense, the histamine H1 receptor inverse agonists desensitize the cAMP response to amthamine, a histamine H2 receptor agonist. In turn, histamine H2 receptor inverse agonists interfere with histamine H1 receptor signaling. We also determine that the crossdesensitization induced by histamine H1 or H2 receptor agonists alters the histamine inverse agonists receptor response: activation of histamine H1 receptor affects cAMP response induced by histamine H2 receptor inverse agonists, whereas histamine H2 receptor agonist induces a negative regulation on the anti-inflammatory response of histamine H1 receptor inverse agonists. Binding studies revealed that histamine H1 and H2 receptors cointernalize after stimulus with histamine receptor inverse agonists. In addition, the inhibition of the internalization process prevents receptor crossregulation. Our study provides new insights in the mechanisms of action of histamine H1 and H2 receptors that explain the effect of histamine H1 and H2 receptor inverse agonists and opens up new venues for novel therapeutic applications.

Evaluation of different classes of histamine H1 and H2 receptor antagonist effects on neuropathic nociceptive behavior following tibial nerve transection in rats.

It seems that histamine release in the site of neuronal injury could contribute to the neuropathic pain mechanism. In the present study, we investigated the anti-allodynic effects of chronic administration of different classes of histamine H1 and H2 receptor antagonists on neuropathic nociceptive behavior following tibial nerve transection (TNT) in rats. Peripheral neuropathy was induced by TNT surgery. We performed acetone tests (AT) to record cold allodynia, Von Frey tests (VFT) to measure mechanical allodynia, double plate test (DPT) to evaluate thermal place preference/avoidance and open field test (OFT) for evaluation of animal activity. TNT rats showed a significant mechanical and cold allodynia compared to the sham group. Chlorpheniramine (5 and 15 mg/kg, i.p) significantly attenuated cold allodynia and prevented cold plate avoidance behavior and at the dose of 15 mg/kg remarkably decreased mechanical allodynia. Fexofenadine (10 and 30 mg/kg, p.o) significantly attenuated the mechanical allodynia and prevented cold plate avoidance. Ranitidine (5 and 15 mg/kg, i.p) significantly prevented cold plate avoidance behavior and at the dose of 15 mg/kg notably improved mechanical and cold allodynia. Famotidine (1 and 3 mg/kg, p.o) was ineffective on all nociceptive tests. Gabapantin (100 mg/kg, p.o) significantly improved all types of nociceptive behaviors. These results indicate that both blood brain barrier penetrating (chlorpheniramine) and poorly penetrating (fexofenadine) histamine H1 receptor antagonists could improve the neuropathic pain sign, but only the blood brain barrier penetrating histamine H2 receptor antagonist (ranitidine) could produce anti-allodynic effects in the TNT model of neuropathic pain in rats.

The role of histamine H1, H2 and H3 receptors of ventral posteromedial nucleus of thalamus in modulation of trigeminal pain.

Histamine receptors are involved in supraspinal modulation of pain. In the present study, we investigated the effects of microinjection of histamine H1, H2 and H3 receptor antagonists and agonists into the ventral posteromedial (VPM) nucleus of the thalamus on two models of trigeminal pain. Right and left sides of VPM were implanted with two guide cannulas. Corneal pain was induced by local corneal surface application of hypertonic saline and the number of eye wipes was recorded. The duration of face rubbing, as an orofacial pain measure, was recorded after subcutaneous (s.c.) injection of capsaicin into the vibrissa pad. 2-pyridylethylamine (2-PEA, a histamine H1 receptor agonist, 4µg/site) and dimaprit (a histamine H2 receptor agonist, 1 and 4µg/site) suppressed corneal and orofacial pains. Mepyramine (a histamine H1 receptor antagonist) and ranitidine (a histamine H2 receptor antagonist) at the similar doses of 0.5, 2 and 8µg/site alone had no effects on trigeminal pain. Prior microinjection of mepyramine and ranitidine at a similar dose of 8µg/site inhibited the antinociceptive effects of 2-PEA (4µg/site) and dimaprit (4µg/site), respectively. Immepip (a histamine H3 receptor agonist, 1 and 4µg/site) increased, and thioperamide (a histamine H3 receptor antagonist, 2 and 8µg/site) attenuated nociceptive responses. Prior microinjection of thioperamide (8µg/site) prevented immepip (4µg/site)-induced nociception. These chemicals did not change locomotor behavior. It is concluded that post-synaptic histamine H2, and to a lesser extent H1, receptors and pre-synaptic histamine H3 receptor may be involved in VPM modulation of trigeminal pain.

In vitro study of histamine and histamine receptor ligands influence on the adhesion of purified human eosinophils to endothelium.

It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood. The viability and functional integrity of isolated eosinophils have been validated in several tests. Histamine as well as 4-methylhistamine (selective H4 agonist) in concentration-dependent manner significantly increased number of eosinophils that adhere to endothelium. Among the selective histamine receptors antagonist or H1 inverse agonist only JNJ7777120 (histamine H4 antagonist) and thioperamide (dual histamine H3/H4 antagonist) had direct effect on eosinophils adhesion to endothelial cells. Antagonists of H1 (diphenhydramine, mepyramine) H2 (ranitidine and famotidine) and H3 (pitolisant) histamine receptors were ineffective. To the best of our knowledge, this is the first study to demonstrate that histamine receptor H4 plays a dominant role in histamine-induced eosinophils adhesion to endothelium.

Further evidence for the role of histamine H3, but not H1, H2 or H4, receptors in immepip-induced inhibition of the rat cardioaccelerator sympathetic outflow.

Since histamine H3 and H4 receptors are coupled to heterotrimeric Gi/o proteins, a signal transduction pathway associated with inhibition of neurotransmitter release, the present study has investigated the inhibition of the rat cardioaccelerator sympathetic outflow induced by the H3/H4 receptor agonist immepip by using antagonists for histamine H1 (ketotifen), H2 (ranitidine), H3 (thioperamide) and H4 (JNJ7777120) receptors. For this purpose, 102 male Wistar rats were pithed, artificially ventilated and prepared for either preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic outflow (n=90) or i.v. bolus injections of noradrenaline (n=12). This approach resulted in frequency-dependent and dose-dependent tachycardic responses, respectively. I.v. continuous infusions of immepip (3 and 10 µg/kg min), but not of saline (0.02 ml/min), dose-dependently inhibited the sympathetically-induced tachycardic responses. Moreover, the cardiac sympatho-inhibition induced by 10 µg/kg min immepip (which failed to affect the tachycardic responses to i.v. noradrenaline) was: (i) unaltered after i.v. treatment with 1 ml/kg vehicle, 100 µg/kg ketotifen, 3000 µg/kg ranitidine, 30 µg/kg thioperamide or 300 µg/kg JNJ7777120; and (ii) abolished after 100 µg/kg thioperamide (i.v.). These doses of antagonists, which did not affect per se the sympathetically-induced tachycardic responses, were high enough to block their respective receptors. In conclusion, the cardiac sympatho-inhibition induced by 10 µg/kg.min immepip involves histamine H3 receptors, with further pharmacological evidence excluding the involvement of H1, H2 and H4 receptors.

Formulation and characterization of sustained release dosage form of moisture sensitive drug.

OBJECTIVE: The purpose of this study was to prepare sustained release tablet of moisture sensitive drug like Ranitidine Hydrochloride for treatment of gastroesophageal reflux disease along with the improvement of moisture stability to get better therapeutic efficacy. MATERIALS AND METHODS: Pan coating technique was used for coating of the tablet. Film coating was done using Eudragit RLPO and Eugragit EPO as coating polymer. 3(2) full factorial design was applied for optimization purpose, and 9 runs were conducted. In that Eudragit RLPO and Eudragit EPO taken as an independent variables and moisture gain and Cummulative Drug Release (CDR) were taken as dependent variables. Drug and excipient compatibility was done using differential scanning calorimetry and Fourier transform infrared spectroscopy study. The tablet was evaluated for precompression parameter and all postcompression parameter. Stability study was carried out at room temperature (30°C ± 2°C/65% ± 5% relative humidity). Final formulation was compared with marketed formulation RANTEC 300. RESULT: Tablets were passing out all precompression parameter along with postcompression parameter. Stability study shows that the parameter such as hardness, friability, and dissolution are in the range. Hence, there is no significant change shown after stability study. Our final formulation was compared with marketed formulation RANTEC 300 and result demonstrates that our final formulation have less moisture gain and give release up to 12 h. CONCLUSION: The result of present study demonstrates that final formulation has less moisture gain and getting desired CDR for sustained release of drug. On the basis of all study, it was concluded that the tablet was coated by combination of Eudragit RLPO 10% and Eudragit EPO 10% give better result. This formation provided promising approach for the drug release up to 12 h for moisture sensitive drug like ranitidine hydrochloride.

Pharmacological evidence that histamine H3 receptors inhibit the vasodepressor responses by selective stimulation of the rat perivascular sensory CGRPergic outflow.

This study has investigated whether pharmacological activation of Gi/o coupled histamine H3/H4 receptors inhibits the rat vasodepressor sensory outflow. For this purpose, 100 male Wistar rats were pithed, artificially ventilated and pretreated (i.v.) with: 25mg/kg gallamine, 2mg/kg/min hexamethonium and 20µg/kg/min methoxamine, followed by i.v. continuous infusions of physiological saline (0.02ml/min) or immepip (3.1, 10 or 31µg/kg/min; a histamine H3/H4 receptor agonist). Under these conditions, electrical stimulation (0.56-5.6Hz; 50V and 2ms) of the spinal cord (T9-T12) resulted in frequency-dependent vasodepressor responses, which were: (i) unchanged during the infusions of saline or immepip (3.1µg/kg/min); and (ii) significantly but, surprisingly, not dose-dependently inhibited by 10 and 31µg/kg/min immepip. Moreover, the sensory-inhibition by 10µg/kg/min immepip (which failed to inhibit the vasodepressor responses by i.v. bolus injections of α-CGRP; 0.1-1µg/kg) was: (i) essentially unaltered after i.v. administration of saline (1ml/kg) or blocking doses of the antagonists ketotifen (100µg/kg; H1), ranitidine (1000µg/kg; H2) or JNJ7777120 (310µg/kg; H4); and (ii) abolished after i.v. thioperamide (310µg/kg; H3). In conclusion, our results suggest that immepip-induced inhibition of the vasodepressor sensory outflow is mainly mediated by prejunctional activation of histamine H3 receptors.

A novel in situ gel formulation of ranitidine for oral sustained delivery.

The main purpose of this study was to develop a novel, in situ gel system for sustained delivery of ranitidine hydrochloride. Ranitidine in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of preparation, viscosity and in vitro release. The viscosity of the gellan gum formulations in solution increased with increasing concentrations of gellan gum. In vitro study showed that the release of ranitidine from these gels was characterized by an initial phase of high release (burst effect) and translated to the second phase of moderate release. Single photon emission computing tomography technique was used to evaluate the stomach residence time of gel containing (99m)Tc tracer. The animal experiment suggested in situ gel had feasibility of forming gels in stomach and sustained the ranitidine release from the gels over the period of at least 8 h. In conclusion, the in situ gel system is a promising approach for the oral delivery of ranitidine for the therapeutic effects improvement.

Formulation and in vitro evaluation of floating tablets of hydroxypropyl methylcellulose and polyethylene oxide using ranitidine hydrochloride as a model drug.

The present study was carried out with an objective of preparation and in vitro evaluation of floating tablets of hydroxypropyl methyl cellulose (HPMC) and polyethylene oxide (PEO) using ranitidine hydrochloride as a model drug. The floating tablets were based on effervescent approach using sodium bicarbonate a gas generating agent. The tablets were prepared by dry granulation method. The effect of polymers concentration and viscosity grades of HPMC on drug release profile was evaluated. The effect of sodium bicarbonate and stearic acid on drug release profile and floating properties were also investigated. The result of in vitro dissolution study showed that the drug release profile could be sustained by increasing the concentration of HPMC K15MCR and Polyox WSR303. The formulation containing HPMC K15MCR and Polyox WSR303 at the concentration of 13.88% showed 91.2% drug release at the end of 24 hours. Changing the viscosity grade of HPMC from K15MCR to K100MCR had no significant effect on drug release profile. Sodium bicarbonate and stearic acid in combination showed no significant effect on drug release profile. The formulations containing sodium bicarbonate 20 mg per tablet showed desired buoyancy (floating lag time of about 2 minutes and total floating time of >24 hours). The present study shows that polymers like HPMC K15MCR and Polyox WSR303 in combination with sodium bicarbonate as a gas generating agent can be used to develop sustained release floating tablets of ranitidine hydrochloride.