The Impact of Volume of Dissolution Medium for Biopredictive Dissolution/Permeation Studies of Enabling Formulations: A Comparison of Two Brands of Telmisartan / Amlodipine Tablets

For compendial dissolution testing of solid dosage forms, media volumes of 500 to 900 mL are used in apparatus I and II to ensure sink conditions. However, these volumes are considerably larger than those in the gastrointestinal tract. Thus, the experiments are not biomimetic and possibly not suitable for biopredictive dissolution testing. The present study investigates the influence of volumes of dissolution media in non-compendial dissolution/permeation settings. Dissolution/permeation studies of two commercial bilayer tablets (Twynsta® and Arrow) containing the active pharmaceutical ingredients telmisartan (40 mg) and amlodipine (10 mg) were evaluated using the MacroFlux tool with various biomimetic media mimicking fasted and fed states as well as biological variability (“biorelevant”). Particularly, the two-stage dissolution process of telmisartan from the tablets is interesting because the compound has a pH-dependent solubility, and 2-stage dissolution leads to supersaturation and precipitation upon pH shift.

For telmisartan, lower dissolution volumes significantly induced precipitation, leading to lower permeation, while no precipitation was observed in the larger volume. The permeation of telmisartan was overly sensitive to both pH and micelle concentrations in the biomimetic media. Amlodipine showed complete dissolution under any conditions, which correlates with its known complete absorption in vivo.

In conclusion, volumes of dissolution media (and their compositions) are key parameters and play a significant role for designing relevant biomimetic experiments used to predict the bioavailability of supersaturating systems.

Introduction

Compendial and internationally harmonized in vitro tests ensure consistent quality standards for pharmaceutical products on the global market. One of the most indicative compendial tests for solid dosage forms is the dissolution test, in which the release of API from drug products is monitored in a standardized apparatus and setting1. As a standard in quality control, the volumes of dissolution media are typically between 500 and 900 mL2. For quality control purposes, large volumes of medium are chosen to achieve sink conditions to ensure rather low concentrations of dissolved API during the entire duration of the test, keeping the concentration gradient to the bulk liquid practically constant. Thus, slowing down API dissolution due to increased API concentration in the medium is avoided, and sink methods are independent of API solubility restrictions. Sink methods are discriminative with respect to product quality and process parameters1.

Data obtained from dissolution tests have also been used to predict in vivo performance, e.g. oral bioavailability, of drug products of poorly soluble drug compounds, where the bioavailability is limited by the dissolution rate or solubility of the API3, 4, 5, 6. However, care must be taken when comparing dissolution results to the in vivo behavior of the dosage forms because there are fundamental differences in terms of volumes, transit times, degree of agitation, etc., compared to the conditions in vivo after oral intake.

In predictive settings, alternative media may be used, such as biomimetic media to reflect gastric and intestinal conditions (“biorelevant”)7. Also, their volumes may be reduced to match in vivo conditions better. Gastric volumes are typically 0.4-0.6 mL/kg in fasted condition, i.e. approx. 40mL in adults8. When administering solid drug products in the context of clinical studies, water volumes of 100-250 mL are usually administered together with the solid dosage form9,10. Using appropriate volumes of dissolution media is particularly important for drugs in classes 2 and 4 of the biopharmaceutics classification system, i.e. poorly soluble drugs, as these are expected to be absorbed under non-sink conditions in vivo11. Defined apparatus and procedures are needed for the smaller volumes. Therefore, in addition to the compendial small volume vessels of 250 mL (Chinese Pharmacopeia), a range of even smaller dissolution vessels to be adjusted to USP App. I and II are available (e.g. 100 mL and 200 mL), in order to develop biomimetic dissolution setups which mimic better the in vivo situations. Using a higher volume in a predictive setting, however, may also be adequate, and in this case, it is an active decision by the analyst designing the experiment.

A common limitation of all bio-predictive dissolution tests is, that the apparently dissolved drug compound is separated from non-dissolved drug by filtration or bench top centrifugation: these methods do not differentiate between the fraction of dissolved drug in free form (“molecularly dissolved”) or associated to colloids (apparently dissolved, solubilized)12. Molecularly dissolved species (i.e., molecules surrounded by their hydration shells) are more prone to permeate biological barriers as compared to solubilized species13. Solubilized molecules are dissolved by interaction with other substances, forming colloidal structures such as micelles, polymer adducts, or inclusion complexes (e.g., cyclodextrin). The drug associated with such colloidal structures does not permeate the intestinal barrier as such, but rather upon redistribution of the drug molecule from the colloidal associate into solution in their free form, a process typically leading to a much lower permeation rate13. Experimental differentiation between the colloid-associated drug fraction and the free drug fraction, which is molecularly dissolved has only recently become analytically accessible in dynamic (non-static) dissolution set-ups by the introduction of microdialysis to in-vitro dissolution testing12,14,15.

Despite its advantages, microdialysis has not yet found widespread use. Instead, in vitro tools that include permeation (combined dissolution/permeation testing) may serve as a surrogate to circumvent the need to distinguish free and solubilized drugs. This is why combined dissolution/permeation tools have recently gained high interest16, 17, 18. However, dissolution/permeation tests are not standardized (yet) in the same manner as dissolution tests described in pharmacopeiae. They come in numerous variants and formats, from larger tools that test a full drug product in a compendial dissolution vessel with an attached permeation chamber (e.g. MacroFlux)19 to high-throughput tools with small sample volumes in 96-well plates20.

In the present study, commercially available telmisartan tablets have been used. This drug substance has a very peculiar and interesting pH dependency of solubility and a tendency to form supersaturated solutions as indicated by the large difference between the thermodynamic and kinetic solubilities21. The drug is available in combination tablets with amlodipine besylate, a drug substance that forms many polymorphs and is well soluble22. This type of combination medication, containing amlodipine and telmisartan, is used in the treatment of hypertension. Two commercially available layer tablet formulations have been studied: Twynsta® from Boehringer Ingelheim GmbH and a generic telmisartan/amlodipine tablet from Arrow Génériques.

According to the patient information leaflets, pH modifiers (sodium hydroxide and meglumine; see supplementary material) are present in both tablets. It is known that in the presence of these excipients, telmisartan appears to be able to form amorphous solid material21,23, 24, 25. Thus, the working hypothesis is that telmisartan may form amorphous states.

In the gastric step of a biomimetic dissolution experiment, the drug substance, which is a base, would be expected to dissolve completely. However, the presence of the pH modifier may slow down this process. Due to its limited solubility at higher pH values (towards neutral), telmisartan may potentially precipitate during/upon transfer into the intestine. As precipitation from supersaturated solutions is a kinetically driven process, this process may be affected by gastric and intestinal conditions regarding composition of media, motility, and gastric emptying profiles in vivo and in vitro in addition to mixing conditions of the media and concentration gradients.

Thus, the current study aimed to assess the impact of varying volumes on biopredictive dissolution/permeation testing using Twynsta® as a model formulation, to simulate in vivo conditions and estimate variability. We compared the results in various biomimetic media and with Arrow’s generic tablet. The results were compared to other similar in vitro studies and to clinical data.

Download the full article as PDF here The Impact of Volume of Dissolution Medium for Biopredictive Dissolution/Permeation Studies of Enabling Formulations

or read it here

Materials

Amlodipine as besylate salt (99.7% purity) and Twynsta tablets (40 mg telmisartan, 10 mg amlodipine) were obtained from Boehringer Ingelheim (Ingelheim, Germany). Telmisartan (Ph. Eur. quality), Methanol (Ph. Eur. quality) and trifluoracetic acid (99% purity), Sodium chloride (Ph. Eur. quality), sodium phosphate dibasic dihydrate (Emsure quality), and acetic acid (Ph. Eur. quality) were purchased from Merck KgaA (Darmstadt, Germany). Telmisartan/amlodipine (40 mg/ 10 mg) tablets were purchased from Arrow Génériques (Lyon, France), referred to as Arrow tablets throughout the manuscript. Vitamin E polyethylene glycol succinate (TPGS) was purchased from BASF Co., Ltd. (Ludwigshafen, Germany). “FaSSIF/FeSSIF/FaSSGF” powder was purchased from Biorelevant (London, United Kingdom). Hydrochloric acid (analytical grade) was purchased from Fischer Scientific (Loughborough, United Kingdom). Sodium phosphate monobasic monohydrate (≥ 98% purity) and NaOH (≥ 99% purity) were purchased from Carl Roth GmbH (Karlsruhe, Germany). Citric acid (≥ 99% purity) was purchased from Acros Organics (Geel, Belgium). Deionized water was used to prepare the media.

Jonas Borregaard Eriksen, Johanna Milsmann, Martin Brandl, Annette Bauer-Brandl, The Impact of Volume of Dissolution Medium for Biopredictive Dissolution/Permeation Studies of Enabling Formulations: A Comparison of Two Brands of Telmisartan / Amlodipine Tablets, Journal of Pharmaceutical Sciences, 2024, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2024.12.010.

---

Are you looking for excipients in commercial quantities?