An in vitro absorption test apparatus for drugs following two-compartment pharmacokinetics, featuring a peripheral compartment simulation and method thereof

Abstract

An in vitro absorption test apparatus for drugs following two-compartment pharmacokinetics, featuring a peripheral compartment simulation and method thereof An in vitro absorption testing apparatus and method for simulating in vivo drug absorption for drugs following two-compartment pharmacokinetics after oral administration are disclosed. The apparatus includes a reservoir vessel containing a dissolution medium, a dissolution vessel with controlled stirring by a rotating element, and an absorption vessel equipped with a magnetic stirrer and overflow system. Fluid flows from the reservoir to the dissolution vessel to replicate the drug's absorption rate constant (Ka) and subsequently into the absorption vessel, which includes a two-phase system with a water-immiscible organic solvent simulating the peripheral compartment. This setup allows for accurate modeling of two-compartment pharmacokinetics. The apparatus provides adjustable fluid flow rates for the compartments and includes temperature control to maintain in vivo conditions. The method involves transferring dissolution medium into the dissolution vessel, then into the absorption vessel containing both aqueous and organic phases. Samples from aqueous phase are withdrawn at specified intervals and analyzed to generate a drug concentration versus time profile for the central compartment, and computational methods normalize in vitro data to simulate in vivo plasma concentrations. Additionally, computational techniques are applied for in vitro-in vivo correlation (IVIVC) to predict pharmacokinetics of drugs following two-compartment model. FIG 1

Specification

Description:Field of the invention:
[0001] The present disclosure generally relates to the technical field of pharmaceutical technology, specifically to pharmaceutical testing and drug formulation development. More particularly, it pertains to an in vitro absorption testing apparatus for drugs following two-compartment pharmacokinetics and method for evaluating formulations of drugs following two-compartment pharmacokinetics and intended for oral absorption.
Background of the invention:
[0002] Understanding drug absorption and pharmacokinetics is essential for effective drug development. Pharmacokinetic models, especially the two-compartment model, are used to simplify the representation of drug absorption, distribution and elimination, providing critical insights into drug behaviour within the body.

[0003] Present methods of in vitro dissolution tests often fail to accurately mimic in vivo absorption profiles, which limits their predictive power. This disconnect between in vitro and in vivo data creates challenges in estimating therapeutic efficacy and bioavailability for pharmaceutical formulations, particularly for drugs following two-compartment pharmacokinetics.

[0004] Establishing a reliable in vitro-in vivo correlation (IVIVC) is critical in drug product development. A robust IVIVC allows researchers to use in vitro results to predict in vivo drug absorption and distribution behaviour, enabling more efficient formulation adjustments and reducing the need for extensive in vivo testing.

[0005] Existing IVIVC methodologies often lack precision because they do not fully account for drug distribution, physiological fluid dynamics or integrate advanced computational modeling. This gap can lead to discrepancies in drug absorption and distribution predictions, complicating the development and regulatory approval of new formulations.

[0006] To address these limitations, there is a need for an advanced in vitro testing apparatus that can more accurately simulate the absorption and distribution characteristics of drugs following two-compartment pharmacokinetics. Adding a peripheral compartment simulation using a water-immiscible organic solvent denser than water and integrating synchronized fluid dynamics with computational pharmaceutics offers a promising solution for achieving this objective.

[0007] The present invention aims to bridge the gap between in vitro and in vivo drug absorption data of drugs two-compartment pharmacokinetics. By using a specialized apparatus and method that combine using a water-immiscible organic solvent and controlled fluid dynamics with computational pharmaceutics, the invention provides a more precise simulation of two-compartment pharmacokinetics, enhancing the predictive power of in vitro absorption tests.

[0008] A publication reviewed computer-based simulations related to prospective prediction of clinical pharmacokinetics (Chen et al. Application of IVIVE and PBPK modeling in prospective prediction of clinical pharmacokinetics: strategy and approach during the drug discovery phase with four case studies. Biopharm Drug Dispos. 2012 Mar;33(2):85-98. doi: 10.1002/bdd.1769, which is incorporated by reference herein in its entirety). However, it is a review article and does not describe any apparatus or method disclosed in the present invention. Importantly, it does not consider a two-compartment model.

[0009] Another publication reviewed the mechanistic approaches to predicting oral drug absorption (Huang et al. Mechanistic approaches to predicting oral drug absorption. AAPS J. 2009 Jun;11(2):217-24. doi: 10.1208/s12248-009-9098-z, which is incorporated by reference herein in its entirety). However, it is also a review article and does not describe any apparatus or method disclosed in the present invention. Furthermore, it reviews about mechanistic approached and not experimental set up or apparatus to generate data. It mainly reviews about ACAT model on which software for prediction of oral absorption is developed. It does not describe any apparatus for studying oral absorption drugs from dosage forms. Importantly, it does not consider a two-compartment model.

[0010] A published paper described an in vitro pharmacodynamic model using a disposable dialyser unit and computer-controlled devices (Ba et al. New approach for accurate simulation of human pharmacokinetics in an in vitro pharmacodynamic model: application to ciprofloxacin. J Antimicrob Chemother. 2001 Feb;47(2):223-7. doi: 10.1093/jac/47.2.223, which is incorporated by reference herein in its entirety). It describes the use of capillaries, which allows simulation of the same kinetic profile in the central and the peripheral compartments. However, the present disclosure is about an in vitro absorption apparatus for drugs following two-compartment pharmacokinetics. Further, the present disclosure is about controlling flow rate in accordance to absorption rate constant (Ka) which is more realistic and accurate. Importantly, the present invention discloses the use of a water-immiscible organic solvent to simulate peripheral compartment to simulate two-compartment pharmacokinetics, which is not disclosed by the prior art. Moreover, in the prior art, the dosage form is to be placed in the central reservoir for evaluation which is completely against normal physiology. It would be like placing a tablet or capsule in blood. But in the present disclosure, the dissolution vessel will simulate the gastrointestinal tract (GIT) and the absorption vessel will simulate blood and is more realistic. Thus, most importantly, the present disclosure explains the inventive steps of using a water-immiscible organic solvent to simulate peripheral compartment, application of Ka for simulation of absorption profile and the use of a simulated GIT. None of these are considered or disclosed in the prior art.

[0011] An Indian patent (No. 357997 dated 08-February-2021- In vitro pharmacokinetic analyzer: one compartment open model for extravascular administration (oral), which is incorporated by reference herein in its entirety) describes a device for analyzing pharmacokinetics in vitro, which simulates the one-compartment open model to predict how drugs behave in vivo after oral administration. However, the present disclosure is about an in vitro absorption apparatus for drugs following two-compartment pharmacokinetics. Moreover, this prior art discloses a device working mainly dependent of the principles of diffusion of drug. Dialysis units are used in the apparatus to simulate the absorption and elimination processes, using the principles of drug diffusion. This prior art cannot have a controlled system to fix drug absorption rate. Thus, the application of absorption rate constant (Ka) is not possible and not described. Also, this prior art does not describe the working example of the invention and any computational methods for determining the pharmacokinetics. Notably, the present invention explains the use of using a water-immiscible organic solvent to simulate peripheral compartment, and application of Ka for most accurate simulation of absorption profile of a drug from the dosage form. In addition, the present disclosure explains the use of fluid dynamics and computational pharmaceutics in most accurate prediction of absorption profile of a drug. Thus, most importantly, the present disclosure explains the inventive steps of using a water-immiscible organic solvent to simulate peripheral compartment and application of Ka for simulation of absorption profile. None of these are considered or disclosed in the prior art. Specifically, the prior art does not disclose an apparatus for drugs, or their formulations, following a two-compartment pharmacokinetic model.

[0012] An Indian patent application (Application No. 202441084795, An in vitro absorption test apparatus and method for operating the same, which is incorporated by reference herein in its entirety) discloses an in vitro absorption testing apparatus and method for simulating drug absorption kinetics, particularly for drugs following one-compartment pharmacokinetics after oral administration. The apparatus is designed to replicate the in vivo drug absorption rate constant (Ka). However, most importantly, it does not consider a two-compartment model and cannot be used for drugs following two-compartment pharmacokinetics. Further, this prior art does not disclose the use of a water-immiscible organic solvent to simulate peripheral compartment. Thus, the use of a water-immiscible organic solvent to simulate peripheral compartment and application to drugs following two-compartment pharmacokinetics are clear inventive steps of the present invention.

[0013] NONE of the above-mentioned prior arts discloses an absorption apparatus or method for simulating in vivo drug absorption for a drug following two-compartment pharmacokinetics combining the principles of use of a water-immiscible organic solvent to simulate peripheral compartment, absorption rate constant (Ka), fluid dynamics and computational pharmaceutics.



Objectives of the invention:
[0014] The objective of the present invention is to provide an in vitro absorption testing apparatus for drugs following two-compartment pharmacokinetics and method for evaluating formulations of drugs following two-compartment pharmacokinetics and intended for oral absorption, by applying the use of a water-immiscible organic solvent to simulate peripheral compartment, absorption rate constant (Ka), fluid dynamics and computational pharmaceutics.
Summary of the invention:
[0015] The present invention discloses an apparatus and method for the in vitro absorption testing of drugs, or its formulations, following two-compartment pharmacokinetics after oral administration.

[0016] In an aspect, an in vitro absorption testing apparatus is provided to simulate in vivo drug absorption for drugs following two-compartment pharmacokinetics after oral administration. The apparatus includes a reservoir vessel for dissolution medium, a dissolution vessel with controlled stirring, and an absorption vessel with a two-phase system, allowing for more accurate replication of drug absorption characteristics.

[0017] In an aspect, the apparatus facilitates independent adjustment of fluid flow rates between the reservoir, dissolution, and absorption vessels. This setup provides enhanced control over the absorption rate constants (Ka) for both the central and peripheral compartments, improving simulation accuracy for specific pharmacokinetic profiles.

[0018] In an aspect, the absorption vessel includes a water-immiscible organic solvent, such as chloroform or carbon tetrachloride, which forms a stable interface with the aqueous phase. This configuration simulates secondary drug distribution phases, enabling the apparatus to mimic the pharmacokinetic behaviour of drugs with peripheral compartmentalization.

[0019] In an aspect, temperature control features maintain the temperature of both aqueous and organic phases at 37±0.5ºC across all vessels in the apparatus, ensuring consistent in vitro conditions that closely simulate in vivo environments for more reliable pharmacokinetic data.

[0020] In an aspect, the dissolution vessel of the apparatus may be equipped with a rotating element to allow controlled stirring of the dissolution medium. Additionally, the dissolution vessel with the rotating element can be replaced by a compendial dissolution test apparatus, enabling the apparatus to adhere to standard dissolution testing protocols as per regulatory guidelines.

[0021] In an aspect, the apparatus is configured to enable sample withdrawal from the aqueous part of the absorption vessel at specific time intervals. This sampling capability allows for the generation of a drug concentration-time profile, providing valuable data on the absorption characteristics of drug formulations. This feature makes the apparatus particularly suitable for quality control and evaluation of drugs following two-compartment pharmacokinetics and intended for oral delivery.

[0022] In an aspect, a method is provided for simulating in vitro drug absorption kinetics, for drugs following two-compartment pharmacokinetics, using the described apparatus. The method involves introducing a drug or its formulation into a dissolution vessel with controlled stirring, transferring fluid to an absorption vessel that mimics the central and peripheral compartments with the presence of aqueous and organic phases respectively, and withdrawing samples from the aqueous phase at intervals to generate a concentration versus time profile for the central compartment.

[0023] In an aspect, the method includes adjusting the fluid flow rate from the reservoir to the dissolution vessel and from the dissolution vessel to the absorption vessel to match the in vivo absorption rate constant (Ka). This adjustment accurately replicates drug absorption kinetics, aiding in the evaluation of various drug formulations following two-compartment pharmacokinetics.

[0024] In an aspect, the method utilizes computational methods to normalize the in vitro data, aligning it with in vivo pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax). This normalization provides a robust comparison between in vitro and in vivo profiles, enhancing the predictive value of the in vitro testing results for two-compartment pharmacokinetics.

[0025] In an aspect, the method provides in vitro-in vivo correlation (IVIVC), enabling in vitro data to predict in vivo drug absorption post-oral administration for drugs following two-compartment pharmacokinetics. This IVIVC feature enhances the invention's applicability for preclinical and regulatory purposes, where in vitro data forecast in vivo drug absorption.

[0026] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed description of drawings:
[0027] The accompanying drawings, included as part of this specification, depict an embodiment of the invention and, along with the written description, clarify the principles underlying the invention.

[0028] FIG. 1 illustrates the design of the in vitro absorption apparatus (200), in accordance to an exemplary embodiment of the invention. The apparatus comprises a reservoir vessel (202) containing a suitable dissolution medium (204) for the drug, connected via a pump (206) to a dissolution vessel (208), with paddle or basket for rotation (210), where the drug is placed. Additionally, there is an absorption vessel (212) equipped with a magnetic stirrer (214), containing a bead (216) and an overflow system for the excess aqueous dissolution medium (218). The absorption vessel contains a water-immiscible organic solvent (220), which is denser than water, to simulate the peripheral compartment. The reservoir vessel transfers fluid proportional to the absorption rate constant (Ka), flows into the dissolution vessel through a pump. Simultaneously, an equal amount of fluid from the dissolution vessel enters the absorption vessel through another pump (222). Tubes (224) are used for the transport of fluids from one vessel to another.

[0029] FIG. 2 illustrates the comparative drug concentration-time profiles of in vitro data before normalization and in vivo data prepared based on a reported study (Bodalia et al. A comparison of the pharmacokinetics, clinical efficacy, and tolerability of once-daily tramadol tablets with normal release tramadol capsules. J Pain Symptom Manage. 2003 Feb;25(2):142-9., which is incorporated by reference herein in its entirety).

[0030] FIG. 3 illustrates the comparative drug concentration-time profiles of in vitro data after normalization and in vivo data prepared based on a reported study (Bodalia et al. A comparison of the pharmacokinetics, clinical efficacy, and tolerability of once-daily tramadol tablets with normal release tramadol capsules. J Pain Symptom Manage. 2003 Feb;25(2):142-9., which is incorporated by reference herein in its entirety).

[0031] FIG. 4 illustrates the in vitro - in vivo correlation (IVIVC) plot of normalized in vitro data and in vivo data prepared based on a reported study (Bodalia et al. A comparison of the pharmacokinetics, clinical efficacy, and tolerability of once-daily tramadol tablets with normal release tramadol capsules. J Pain Symptom Manage. 2003 Feb;25(2):142-9., which is incorporated by reference herein in its entirety). A good correlation (R2 value of 0.8379) between in vitro and in vivo drug profiles was achieved after normalization, and it implied that the in vitro data could be a reliable predictor of in vivo behaviour.

Detailed invention disclosure:
[0032] Different embodiments of the present invention are described with reference to the accompanying drawings. Where feasible, identical or similar reference numerals are used throughout the drawings and description to denote the same or similar components or steps.

[0033] Embodiment of the present disclosure generally relates to the technical field of pharmaceutical technology, in specific, relates to an apparatus and method for operation for the in vitro absorption testing of drug formulations intended for oral absorption and following two-compartment pharmacokinetics, by using a water-immiscible organic solvent to simulate peripheral compartment and applying in vivo absorption rate constant (Ka), fluid flow and computational pharmaceutics.

[0034] Embodiment of the present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide an apparatus and method for operation for the in vitro absorption testing of drug formulations intended for oral absorption and following two-compartment pharmacokinetics, using a water-immiscible organic solvent to simulate peripheral compartment and by applying in vivo absorption rate constant (Ka), fluid flow and computational pharmaceutics.

[0035] In an embodiment, the invention provides an in vitro absorption testing apparatus designed to simulate in vivo drug absorption kinetics for drugs following two-compartment pharmacokinetics. The apparatus comprises a reservoir vessel containing a dissolution medium, which flows into a dissolution vessel equipped with a rotating element for controlled stirring. A pump is configured to control the fluid transfer from the reservoir vessel to the dissolution vessel, and subsequently to an absorption vessel with a magnetic stirrer and overflow system. The absorption vessel with a two-phase system more accurately simulates a two-compartment system. This configuration allows for replicating the drug's in vivo absorption rate constant (Ka) within a controlled in vitro environment, providing a practical model for two-compartment pharmacokinetic studies.
[0036] In an embodiment, the apparatus includes an adjustable fluid flow system that allows fine-tuning of the flow rate from the reservoir vessel to the dissolution vessel and onward to the absorption vessel. This adjustability is critical to replicate the desired in vivo absorption rate constant (Ka) of various drugs following two-compartment pharmacokinetics. By precisely controlling the flow rates, the system can model different drug release and absorption kinetics, simulating physiological conditions to obtain reliable absorption data for quality control and research purposes.
[0037] In an embodiment, the dissolution vessel in the apparatus is equipped with a rotating element to provide controlled stirring of the dissolution medium. This rotating element may be replaced by a compendial dissolution test apparatus to ensure standardized stirring rates and conditions, allowing the apparatus to comply with regulatory and compendial dissolution testing requirements. The flexibility in stirring apparatus choice makes this invention versatile and suitable for both research and regulatory testing applications of various drugs, and its formulations, following two-compartment pharmacokinetics.
[0038] In an embodiment, the apparatus incorporates temperature control mechanisms across the reservoir, dissolution, and absorption vessels, maintaining a fluid temperature of 37±0.5ºC. This temperature control mimics human body conditions, ensuring that the absorption testing environment is physiologically relevant. The maintained temperature allows for consistent and reproducible testing, which is essential for accurate simulation of in vivo drug absorption kinetics of various drugs, and its formulations, following two-compartment pharmacokinetics.
[0039] In an embodiment, the absorption vessel contains a water-immiscible organic solvent, such as chloroform or carbon tetrachloride, which forms a stable interface with the aqueous phase. This setup mimics secondary distribution phases, allowing the apparatus to simulate the pharmacokinetic behaviour of drugs that distribute into a peripheral compartment. This provides a simulation of two-compartment pharmacokinetics.
[0040] In an embodiment, the apparatus is designed to withdraw samples from the aqueous phase of the two-phase system in the absorption vessel at specified intervals to analyze drug concentration over time. These samples enable the generation of a concentration-time profile that accurately reflects the drug's absorption behaviour in vivo. By simulating the two-compartment pharmacokinetics of a drug formulation, the apparatus is an invaluable tool for quality control and evaluation of oral drug products, allowing researchers to predict in vivo absorption profiles from in vitro data.
[0041] In an embodiment, a method is provided for simulating in vitro drug absorption kinetics for drugs with two-compartment pharmacokinetics using the described apparatus. The method involves introducing a drug or formulation into a dissolution vessel with controlled stirring, transferring fluid to an absorption vessel that mimics both central and peripheral compartments with aqueous and organic phases, respectively, and withdrawing samples from the aqueous phase to generate a concentration versus time profile.
[0042] In an embodiment, the method includes adjusting fluid flow rates from the reservoir to the dissolution vessel and from the dissolution vessel to the absorption vessel, thereby replicating the in vivo absorption rate constant (Ka). This adjustment enables accurate replication of drug absorption kinetics, aiding in the assessment of drug formulations that follow two-compartment pharmacokinetics.
[0043] In an embodiment, the method uses a water-immiscible organic solvent to simulate the peripheral compartment within an in vitro absorption testing apparatus designed for drugs following two-compartment pharmacokinetics. The process begins by introducing a drug or its formulation into a dissolution vessel with a controlled stirring mechanism, after which the dissolved drug solution is transferred to an absorption vessel containing both an aqueous phase, representing the central compartment, and an organic solvent phase, representing the peripheral compartment.
[0044] In an embodiment, computational methods are applied to normalize the in vitro data to match in vivo pharmacokinetic parameters such as maximum concentration (Cmax) and time to reach maximum concentration (Tmax). This normalization process enhances the predictive value of the in vitro testing results, enabling robust comparisons with in vivo profiles for two-compartment pharmacokinetics.
[0045] In an embodiment, the method provides in vitro-in vivo correlation (IVIVC), allowing in vitro data to predict in vivo drug absorption for drugs administered orally and following two-compartment pharmacokinetics. This feature makes the invention highly valuable for preclinical testing and regulatory applications, where accurate in vitro predictions of in vivo drug absorption are crucial.
[0046] According to another exemplary embodiment of the invention, FIG. 1 refers to an illustration of the design of the in vitro absorption apparatus.

[0047] According to another exemplary embodiment of the invention, FIG. 2 refers to a comparative drug concentration-time profiles of in vitro data before normalization and in vivo data prepared based on a reported study for the drug (tramadol hydrochloride) following two-compartment pharmacokinetics.

[0048] According to another exemplary embodiment of the invention, FIG. 3 refers to a comparative drug concentration-time profiles of in vitro data after normalization and in vivo data prepared based on a reported study for the drug following two-compartment pharmacokinetics.

[0049] According to another exemplary embodiment of the invention, FIG. 4 refers to an in vitro - in vivo correlation (IVIVC) plot of normalized in vitro data and in vivo data prepared based on a reported study for the drug following two-compartment pharmacokinetics. A good correlation (R2 value of 0.8379) between in vitro and in vivo drug profiles was achieved after normalization.

[0050] From the present disclosures, it may be apparent that the in vitro absorption apparatus and its method of operation represent novelty by simulating two-compartment pharmacokinetics through the use of an organic solvent-based, two-phase system in the absorption vessel, fluid flow control, and computational pharmaceutics based on the drug's in vivo absorption rate constant (Ka).

[0051] From the present disclosures, it may be apparent that the in vitro absorption apparatus and its method of operation, incorporating the drug's in vivo absorption rate constant (Ka), controlled fluid flow, and a water-immiscible organic solvent to simulate the peripheral compartment in two-compartment pharmacokinetics, are non-obvious compared to prior arts and demonstrate inventive steps.

[0052] From the present disclosures, it may be apparent that the in vitro absorption apparatus and its method of operation can serve as an effective quality control and evaluation tool for pharmaceutical formulations intended for oral administration, specifically by replicating two-compartment pharmacokinetics with industrial applicability.

[0053] It will be clear that various modifications and adjustments can be applied to the apparatus and measurement methods outlined in the preceding example without straying from the core principles of the invention, and all such modifications and adjustments are meant to be included within the scope of this application.

[0054] The following will illustrate in detail specific embodiments of the present invention:
Example: Tramadol hydrochloride tablet with a label claim of 50 mg was taken and placed in the dissolution vessel (208), which contained 600 mL of distilled water as the dissolution medium (204). The rotating element (paddle) (210) of the dissolution vessel was set to 50 rpm. The absorption rate constant value (Ka) of Tramadol hydrochloride is 2.96 per hour as per reported data. During the experiment, 29.6 mL per minute of the dissolution medium, corresponding to 2.96 volume fraction of the dissolution medium per hour (Ka), was transferred from the reservoir vessel (202) to the dissolution vessel using a pump (206). Simultaneously, dissolution medium was transferred from the dissolution vessel to the absorption vessel (212), under magnetic stirring, through the other pump (222) at the same rate of 29.6 mL per minute. The absorption vessel contains a water-immiscible organic solvent (220), which is denser than water, to simulate the peripheral compartment. The excess aqueous fluid from the absorption vessel was expelled through the overflow system (218). At 5-minute intervals, 5 mL samples were taken from the aqueous dissolution medium contained in the absorption vessel and their absorbance was measured using a UV spectrophotometer and determined the concentration of tramadol hydrochloride. The comparative drug concentration-time profiles of in vitro data and in vivo data prepared based on the reported study was prepared (FIG. 2). The in vitro data was then normalized to match the maximum concentration (Cmax) and time to reach the maximum concentration (Tmax) of the in vivo data allowing for a meaningful comparison between the two datasets. Then, the concentration versus time graph was plotted, and it was compared with in vivo data using Python software (FIG. 3). Finally, in vitro-in vivo correlation (IVIVC) was caried out using Python software and a good correlation (R2 value of 0.8379) was observed (FIG. 4). Thus, in vitro data can be used to predict in vivo absorption after oral administration of drugs, and its formulations, following two-compartment pharmacokinetics.
, Claims:I/We Claim:
1. An in vitro absorption testing apparatus for simulating in vivo drug absorption for a drug following two-compartment pharmacokinetics after oral administration, comprising:
a reservoir vessel containing a dissolution medium;
a dissolution vessel with provision for controlled stirring by a rotating element;
the dissolution vessel connected to the reservoir vessel via a pump;
an absorption vessel equipped with a magnetic stirrer and an overflow system, wherein fluid flows from the reservoir vessel to the dissolution vessel to replicate the absorption rate constant (Ka) of the drug under study, and subsequently flows into the absorption vessel;
wherein the absorption vessel contains a water-immiscible organic solvent to simulate the peripheral compartment, providing a two-phase system within the absorption vessel for better simulation of two-compartment pharmacokinetics; and
wherein the apparatus is configured to withdraw samples from the aqueous phase of the absorption vessel at specified intervals for analysis.
2. The apparatus of claim 1, wherein fluid flow rate from the reservoir vessel to the dissolution vessel and subsequently to the absorption vessel can be adjusted to replicate the in vivo absorption rate constant (Ka) of the drug following two-compartment pharmacokinetics.
3. The apparatus of claim 1, wherein the water-immiscible organic solvent is denser than water, selected from a group including chloroform and carbon tetrachloride, and forms a stable phase interface with the aqueous phase in the absorption vessel, accurately mimicking the pharmacokinetic behavior of drugs with distribution to a peripheral compartment.
4. The apparatus of claim 1, further comprising temperature control provisions for maintaining the temperature of both the aqueous and organic phases in the reservoir, dissolution, and absorption vessels at 37±0.5ºC, ensuring accurate simulation of in vivo conditions across both compartments.
5. The apparatus of claim 1, wherein the dissolution vessel with provision for controlled stirring by a rotating element can be replaced by using a compendial dissolution test apparatus.
6. A method for simulating drug absorption kinetics in vitro for a drug following two-compartment pharmacokinetics after oral administration, using a water-immiscible organic solvent to simulate peripheral compartment, applying the in vivo absorption rate constant (Ka) of the drug, controlled fluid flow, and computational pharmaceutics, comprising:
transferring dissolution medium from a reservoir vessel into a dissolution vessel where a drug or formulation is introduced and subjected to controlled stirring by a rotating element;
further transferring fluid to an absorption vessel containing an aqueous phase and a water-immiscible organic solvent simulating the peripheral compartment, wherein fluid flows at a rate replicating the drug's absorption rate constant (Ka);
withdrawing samples from the aqueous phases at specified intervals and analyzing drug concentration to generate a drug concentration versus time profile of the central compartment; and
normalizing the in vitro data using computational methods to simulate in vivo plasma concentration versus time profile.
7. The method of claim 6, wherein fluid flow from the reservoir vessel to the dissolution vessel and subsequently to the absorption vessel is adjusted to replicate drug absorption rate constant (Ka), to reflect absorption kinetics observed in vivo for a drug following two-compartment pharmacokinetics.
8. The method of claim 6, further comprising applying computational methods to normalize the obtained in vitro data to match the maximum concentration (Cmax) and time to reach maximum concentration (Tmax) for central compartment, allowing for a meaningful comparison between the two datasets of a drug following two-compartment pharmacokinetics.
9. The method of claim 6, further comprising applying computational methods to carry out in vitro-in vivo correlation (IVIVC), to predict in vivo drug distribution following oral administration, specifically for a drug following two-compartment pharmacokinetics.

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