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Matthew Perez
Matthew Perez

Usp 724 Drug Release Pdf Download



The typical pH profile and residence times in the stomach and small intestine were determined in fasted conditions based on the published results of swallowable monitoring devices. Then, a multi-stage pH shift dissolution method was developed by adding different amounts of phosphate-based buffer solutions to the initial hydrochloric acid solution. Because of the highly variable in vivo residence times in the stomach, two alternatives of the method were applied, modeling rapid and slow gastric emptying as well. This approach provided an opportunity to study the effect of the acidic treatment on post gastric release. Six enteric-coated low-dose acetylsalicylic acid (ASA) formulations including the reference Aspirin Protect were tested as a model compound. Moreover, the thickness of the coating of each formulation was investigated by scanning electron microscope.




Usp 724 Drug Release Pdf Download



The reliable prediction of in vivo performance of generic formulation candidates is a continuous challenge in drug development. In cases where solubility or the dissolution of the API is the rate limiting factor of absorption, the in vitro dissolution test is the primary tool for the prediction of bioavailability (1). However, conventionally used apparatuses and buffer compositions are usually not suitable to model the complex atmosphere of the gastrointestinal system. The lack of predictive in vitro dissolution methods is particularly common in formulations such as enteric-coated(EC) products, which was underlined by Al-Gousouset al. (2).


The dissolution testing of delayed-release products for quality control (QC) purposes is specified by various Pharmacopoeias. In order to demonstrate the resistance of the coating to the gastric fluid, both EMA and FDA prescribes the testing of the product in an acidic medium (e.g. 0.1 M hydrochloric acid) for 1 to 2 h, which is followed by testing in a buffer solution of pH 6.8 to model the small intestinal environment (3, 4). As evident from the prescriptions of the Pharmacopoeias, these methods apply only one pH to model the small intestine, which is not sufficient to determine the exact site of disintegration and absorption. In general, dissolution methods for QC purposes need to be robust and simple to implement, which limits the in vivo predictability of the method. However, in case the aim is to support the formulation development, dissolution methods should be as biorelevant as possible in order to design the formulation able to behave in vivo as intended.


These results are in agreement with the expectation for delayed release formulations that are designed to release the active substance after the dosage form has reached the small intestine, therefore do not dissolve in acidic media. As the dosage form is placed in the higher-pH environment, the polymer coating dissolves, and the tablet core behaves similarly to immediate-release formulations. Based on the results of the acid phase, the gastro resistance of the enteric coating of each formulation was found to be appropriate. As the pH 6.8 used after the pH change is typical for the jejunum in fasted state, the formulations are expected to dissolve in this intestinal tract at the latest. However, in the absence of a medium modeling the duodenal pH, the results do not provide information about the exact site of the onset of the drug release.


According to the individual USP monograph of Aspirin Delayed-Release Tablets not more than 10% of the labeled amount of aspirin is allowed to dissolve in the acidic stage while the dissolution in the buffer stage must exceed 75% in 45 min (35). These criteria are consistent with both USP and Ph. Eur general prescriptions for delayed-release formulations (36, 37). Based on Fig. 1, it can be determined that all formulations met the acceptance criteria. However, the in vivo studies performed did not demonstrate bioequivalence for either ASA Krka or Asactal formulations (24, 25). The latter also points out the importance of an appropriate biorelevant dissolution method during generic formulation development phase.


The composition of the gastric buffer was 0.01 M HCl solution, while the appropriate pH changes were achieved by the addition of different amounts of Na2HPO4 solutions with different molarities. The molarity of the phosphate-based buffer solutions was set based on the results of Al-Gousouset al., who elaborated a simplified alternative to unstable bicarbonate buffer systems (34). The volume of the dissolution media varied from 160 mL to 210 mL, which better suits the amount of fluid in the stomach after the intake of drugs with a glass of water.


In case of ASA Krka, bioequivalence could not be demonstrated in the fasted state. The study showed 16% increase for both AUC and Cmax compared to the reference product which is consistent with the results of the RGE method, which predicts an earlier release of the ASA Krka formulation compared to Aspirin Protect. The onset of release of ASA Krka obtained from the SGE method is similar to that of Aspirin Protect. However, the slope of its dissolution curve is slightly higher, which generally predicts a higher Cmax value as well. Based on Table I, the applied plasticizer in the coating of this formulation is triacetin, while the reference product is formulated with triethyl citrate, which may explain the different onset of drug release observed with the RGE method. The slightly higher dissolution rate is probably related to the hydrophilic lactose monohydrate in the tablet core.


Applying the new method with longer acidic treatment resulted in later onset and slower rate of post-gastric drug release for all formulations. Considering the high variability of in vivo gastric residence times, performing the dissolution with both alternatives of the new method may be necessary to lower the risk of bioinequivalence of similar generic drug candidates.


Overall, we conclude that the new method can be a good alternative for reaching a better understanding of the post-gastric behavior of enteric-coated formulations which is essential to get appropriate information on intestinal release and bioavailability.


Abstract:The aim of our study was to adapt the analytical quality by design (AQbD) approach to design an effective in vitro release test method using USP apparatus IV with a semi-solid adapter (SSA) for diclofenac sodium hydrogel. The analytical target profile (ATP) of the in vitro release test and ultra-high-performance liquid chromatography were defined; the critical method attributes (CMAs) (min. 70% of the drug should be released during the test, six time points should be obtained in the linear portion of the drug release profile, and the relative standard deviation of the released drug should not be over 10%) were selected. An initial risk assessment was carried out, in which the CMAs (ionic strength, the pH of the media, membrane type, the rate of flow, the volume of the SSA (sample amount), the individual flow rate of cells, drug concentration %, and the composition of the product) were identified. With the results, it was possible to determine the high-risk parameters of the in vitro drug release studies performed with the USP apparatus IV with SSA, which were the pH of the medium and the sample weight of the product. Focusing on these parameters, we developed a test protocol for our hydrogel system.Keywords: analytical quality by design; in vitro release test; USP apparatus IV with semi-solid adapter; topical gel; diclofenac sodium


A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.


It is unknown if this drug passes into breast milk. Similar medications pass into breast milk. Consult your doctor before breast-feeding. Interactions Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (such as prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.


Some products that may interact with this drug are: corticosteroids taken by mouth (such as prednisone). Does betamethasone dipropionate topical interact with other drugs you are taking? Enter your medication into the WebMD interaction checker Check Interaction Overdose This medicine may be harmful if swallowed. If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Notes Do not share this medication with others.


Lab and/or medical tests (such as adrenal gland function) may be done while you are using this medication, especially if you use this drug for an extended period of time or apply it over large areas of the body. Keep all medical and lab appointments. Consult your doctor for more details.


Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use.


The flow-through dissolution method offers complete flexibility on media volumes and allows repeatable positioning of virtually all dosage forms such as powders, APIs, lipophilic forms, suppositories, suspensions, liposomes, microspheres, semi-solids, implants, and medical devices including drug eluting stents. Described in the United States Pharmacopeia (USP) as Apparatus 4, in the European Pharmacopeia (EP) as Flow-through cell, in the Japanese Pharmacopeia (JP) as Apparatus 3, in the Chinese Pharmacopeia (ChP) as Method 6, and other Pharmacopeia, dissolution and drug release testing using a flow-through cell is proven to characterize the active drug release in terms of bioequivalence and in-vitro / in-vivo correlation (IVIVC) in clinical studies and daily QC routines alike.


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