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Study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro
expand article infoNataliia Shulyak‡§, Kateryna Liushuk§, Oksana Semeniuk§, Nadiya Yarema‡, Tetyana Uglyar‡, Dariya Popovych‡, Andriy Sverstiuk‡, Roman Ciciura‡, Liliya Logoyda‡
‡ I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
§ Municipal Institution of Higher Education «Volyn Medical Institute» of the Volyn Oblast Counsil, Lutsk, Ukraine

Corresponding author: Liliya Logoyda ( logojda@tdmu.edu.ua )

Academic editor: Plamen Peikov
© 2022 Nataliia Shulyak, Kateryna Liushuk, Oksana Semeniuk, Nadiya Yarema, Tetyana Uglyar, Dariya Popovych, Andriy Sverstiuk, Roman Ciciura, Liliya Logoyda.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Shulyak N, Liushuk K, Semeniuk O, Yarema N, Uglyar T, Popovych D, Sverstiuk A, Ciciura R, Logoyda L (2022) Study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro. Pharmacia 69(1): 61-67. https://doi.org/10.3897/pharmacia.69.e77319
Open Access

Abstract

Atorvastatin and lisinopril are a successful combination for the treatment of patients with chronic heart failure and hypertension. Study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro were described. In medium with hydrochloric acid pH 1.2, in the medium of acetate buffer solution with a pH of 4.5 and in the medium phosphate buffer solution with a pH of 6.8 for 15 min more than 85% of the active substance passes into solution, hence the dissolution profiles these drugs in these environments are similar, and the drugs in them are “very quickly soluble”. Among the in vitro models that make it possible to assess the degree of absorption of API, the most widely used culture of adenocarcinoma cells of the colon – Caco-2. The development of the analytical methodology and its validation is the final stage of both the dissolution study and the Caco-2 test, as well as the biowaver procedure. It plays the most important role in the reliability of the results for all the above procedures and tests. To study permeability, method LC-MS/MS was developed. According to the obtained results, atorvastatin and lisinopril showed low permeability. The values ​​of recovery of transport of test and control substances through the monolayer of cells of the Caco-2 line indicate that the results of the experiment can be considered reliable. The equivalence of the drugs “Lisinopril”, tablets of 10 mg and “Atorvastatin”, tablets of 10 mg, belongs to class III BCS proven by in vitro studies.

Keywords

Atorvastatin, Dissolution study, Lisinopril, Recovery, Permeability

Introduction

Ensuring the quality of treatment largely depends on the bioavailability of the drug, which in turn is influenced by the correct and effective pharmaceutical development. Determination of bioavailability and assessment of bioequivalence are important elements in the development and state registration of a medicinal product. Understanding the process of drug delivery to an organ or target cell is one of the tasks of modern pharmacy. In order for the drug to reach the systemic bloodstream, it goes through many stages, namely release from the dosage form, dissolution in the physiological environment of the gastrointestinal tract, absorption through the gastric membrane. Analytical methods should be developed and validated to quantify the concentration of API in solution. These are usually spectrophotometry and high performance liquid chromatography (HPLC). Carrying out the classical test “Dissolution” is insufficient for many purposes, it is necessary to study the dissolution kinetics of the drug. The trend of modern biopharmacy is the biowaver procedure, the approach of which on the basis of the biopharmaceutical classification system is designed to replace bioequivalence studies in vivo. Pharmacokinetic studies are complicated when, in order to increase the effectiveness of pharmacotherapy of any disease, the patient is prescribed several drugs simultaneously or the objects of study of bioequivalence are multicomponent dosage forms. Reliable and objective analytical studies at the stage of pharmaceutical development and implementation allow to ensure proper bioavailability and, as a consequence, the expected therapeutic effect of the drug. All this will optimize the pharmaceutical development of drugs and improve the effectiveness and safety of treatment, as well as patient compliance with pharmacotherapy.

Atorvastatin and lisinopril are a successful combination for the treatment of patients with chronic heart failure and hypertension (Naveed 2015; GoodRx undated). Analytical methods of analysis (Leis et al. 1998, 1999; El Gindy et al. 2001; Andreas et al 2003; El-Emam et al. 2004; Beasley et al. 2005; Rahman et al. 2005a, 2005b; Huang et al. 2006; Stanisz and Kania 2006; Chaudhari et al. 2007; Ivanovic et al. 2007; Shah et al. 2007; Basavaiah et al 2009; Chauhan et al. 2011; Jamakhandi et al. 2011; Sultana et al. 2011; Kumar et al. 2012; Naveed et al. 2012; Arayne et al 2013; Hafez et al. 2014; Lakshmi and Sreedevi 2014; Sathiyasundar and Valliappan 2014; Sbârcea et al. 2014; Shulyak et al. 2021a, 2021b, 2021c) have been developed for the determination of atorvastatin and lisinopril in medicines and biological liquids. However, many of these methods are limited in their usage. There is, therefore, a need for a rapid simple green spectrophotometric and chromatographic methods for the assay of atorvastatin and lisinopril for in vitro bioequivalence study.

The present paper describes the study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro with usage of spectrophotometric and chromatographic methods for the determination of atorvastatin and lisinopril.

Aim of work

We aimed to study the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro.

Materials and methods

Reagents and standards

All the chemicals were used of analytical reagent grade.

Atorvastatin calcium (purity 99.1%) and lisinopril (purity 99.3%) were purchased from Sigma-Aldrich (Switzerland).

The used dosage forms of lisinopril: Lisinopril (10 mg) (Tablets A), Lisinopril (10 mg) (Tablets B), Lisinopril (10 mg) (Tablets C).

The used dosage forms of atorvastatin: Atorvastatin (10 mg) (Tablets A), Atorvastatin (10 mg) (Tablets B), Atorvastatin (10 mg) (Tablets C).

Apparatus

A double – beam Shimadzu UV-Visible spectrophotometr, with spectral bandwidth of 1 nm wavelength accuracy ±0.5 nm, Model –UV 1800, Software UV-Probe 2.62, and a pair of 1 cm matched quartz cells, was used to measure absorbance of the resulting solution. Designed in accordance with the governing Japanese and European Pharmacopoeia, the new UV-1800 UV-VIS spectrophotometer achieves a resolution of 1 nm, the highest in its class, in a compact design.

All LC measurements were performed using Shimadzu VP HPLC system including vacuum degasser, gradient pumps, column oven and autosampler. The LC system was coupled with tandem mass spectrometer API 3000 (PE Sciex). The TurboIonSpray ion source was used in both positive and negative ion modes. Parameters of electrospray ionizer and MRM parametrs are listed in Table 1. Acquisition and analysis of the data were performed using Analyst 1.5.2 software (PE Sciex).

Table 1.
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Parameters of electrospray ionization.

Parameter Value
Polarity Positive
Nebulizer Gas (NEB, Gas 1) 15
Curtain Gas (CUR) 8
Collision Gas (CAD) 5
IonSpray Voltage (IS) 5000
Temperature (TEM) 400
Turbo IonSpray Gas 8
Horizontal Position 5.0
Lateral Position 1.0

Stationary phase was a reversed –phase column Discovery C18, 50 × 2.1 mm, 5 μm. Eluent A: acetonitrile – H2O – formic acid (5: 95: 0.1); eluent B: acetonitrile – formic acid (100: 0.1).

Parameters of acqusition method atorvastatin

Samples were chromatographed in gradient mode. The initial content of eluent B was 10%, which linearly increases to 100% in 1.0 min and in 1.11 min returns to the original 10%. Eluent consumption – 0.4 mL/min; column thermostat temperature – 30 °C; registration time – 2.5 minutes; the volume of the injected sample – 2 μl; autosampler thermostat temperature – 15 °C. Multiple reaction monitoring (MRM) parameters of atorvastatin are presented in Table 2.

Table 2.
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Multiple reaction monitoring (MRM) parameters of atorvastatin.

Analyte Parent, m/z Daughter, m/z Time, ms DP, V EP, V CE, V CXP, V
Atorvastatin 559.234 440.300 120 96 370 11 29

* Abbreviations: DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, collision cell exit potential.

Parameters of acqusition method lisinopril

Samples were chromatographed in gradient mode. The initial content of eluent B was 0%, which linearly increases to 100% in 1.2 min and in 1.31 min returns to the original 0%. Eluent consumption – 0.4 mL/min; column thermostat temperature – 30 °C; registration time – 2.8 minutes; the volume of the injected sample – 2 μl; autosampler thermostat temperature – 15 °C. Multiple reaction monitoring (MRM) parameters of lisinopril are presented in Table 3.

Table 3.
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Multiple reaction monitoring (MRM) parameters of lisinopril.

Analyte Parent, m/z Daughter, m/z Time, ms DP, V EP, V CE, V CXP, V
Lisinopril 406.145 84.2 120 91 11 43 4

* Abbreviations: DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, collision cell exit potential.

Parameters of acqusition method atenolol

Samples were chromatographed in gradient mode. The initial content of eluent B was 0%, which linearly increases to 90% in 1.1 min and up to 1.11 min returns to the original 0%. Eluent consumption – 0.4 mL/min; column thermostat temperature – 30 °C; registration time – 2.3 minutes; the volume of the injected sample – 3 μl; autosampler thermostat temperature – 15 °C. Multiple reaction monitoring (MRM) parameters of atenolol are presented in Table 4.

Table 4.
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Multiple reaction monitoring (MRM) parameters of atenolol.

Analyte Parent, m/z Daughter, m/z Time, ms DP, V EP, V CE, V CXP, V
Atenolol 267.026 145.1 120 56 11 37 12

* Abbreviations: DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, collision cell exit potential.

Parameters of acqusition method propranolol

Samples were chromatographed in gradient mode. The initial content of eluent B was 10%, which linearly increases to 100% in 1.0 min and to 1.01 min returns to the original 10%. Eluent consumption – 0.4 mL/min; column thermostat temperature – 30 °C; registration time – 2.2 minutes; the volume of the injected sample – 3 μl; autosampler thermostat temperature – 15 °C. Multiple reaction monitoring (MRM) parameters of propranolol are presented in Table 5.

Table 5.
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Multiple reaction monitoring (MRM) parameters of propranolol.

Analyte Parent, m/z Daughter, m/z Time, ms DP, V EP, V CE, V CXP, V
Propranolol 260.1 183.4 100 56 11 27 16

* Abbreviations: DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, collision cell exit potential.

Parameters of acqusition method quinidine

Samples were chromatographed in gradient mode. The initial content of eluent B 0%, which linearly increases to 100% in 1.0 min and up to 1.01 min returns to the original 0%. Eluent consumption – 0.4 ml / min; column thermostat temperature – 30 °C; registration time – 2.4 minutes; the volume of the injected sample – 3 μl; autosampler thermostat temperature – 15 °C. Multiple reaction monitoring (MRM) parameters of quinidine are presented in Table 6.

Table 6.
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Multiple reaction monitoring (MRM) parameters of quinidine.

Substance Parent, m/z Daughter, m/z Time, ms DP, V EP, V CE, V CXP, V
Quinidine 325.2 172.2 150 61 11 47 28

* Abbreviations: DP, declustering potential; EP, entrance potential; CE, collision energy; CXP, collision cell exit potential.

Cultivation of Caco-2 cells

Caco-2 cells were cultivated in 75 cm2 flasks to 70–80% of confluence according to the ATCC and Millipore recommendations in humidified atmosphere at 37 °C and 5% CO2. Cells were detached with Trypsin/EDTA solution and resuspended in the cell culture medium to a final concentration of 2×105 cells/ml. 500 µl of the cell suspension was added to each well of HTS 24-Multiwell Insert System and 35 ml of prewarmed complete medium was added to the feeder tray. Caco-2 cells were incubated in Multiwell Insert System for 21 days before the transport experiments. The medium in filter plate and feeder tray was changed every other day. After 21 days of cell growth, the integrity of the monolayer was verified by measuring the transepithelial electrical resistance (TEER) for every well using the Millicell-ERS system ohm meter. The final TEER values were within the range 150–600 Ω×cm2 as required for the assay conditions. 24-well insert plate was removed from its feeder plate and placed in a new sterile 24-well transport analysis plate. The medium was aspirated and inserts washed with PBS twice (Arena and Phillips 2003; Sevin et al 2013; Srinivasan et al 2015; Logoyda 2018).

Procedure

To determine the rate of compounds transport in apical (A) to basolateral (B) direction, 300 µL of the test compound dissolved in transport buffer at 10 µM (HBSS, 10 mM HEPES, pH=7.4) was added into the filter wells; 1000µL of buffer (HBSS, 10 mM HEPES, pH=7.4) was added to transport analysis plate wells. The plates were incubated for 90 min at 37 °C with shaking at 100 RPM. 75 µL aliquots were taken from the donor and receiver compartments for LC-MS/MS analysis. All samples were mixed with 2 volumes of acetonitrile with following protein sedimentation by centrifuging at 10000 rpm for 10 min. Supernatants were analyzed using the LC system coupled with tandem mass spectrometer. Propranolol (high permeability), atenolol (low permeability) and quinidine (moderate permeability) were used as reference compounds (Arena and Phillips 2003; Sevin et al 2013; Srinivasan et al 2015; Logoyda 2018).

Permeability coefficient (Papp) was calculated for Caco-2 permeability assay using the following equation:

Papp=VAArea×time×[drug]acc[drug]initial donor*1000000

VA – volume of transport buffer in acceptor well (1.0 cm3 in the test A → B; 0.3 cm3 in the test B → A),

Area – surface area of the insert (equals to effective growth area of the insert – 0.7 cm2),

Time – time of the assay (5400 sec),

[drug]acc – concentration of test compound in acceptor well,

[drug]initial,d – initial concentration of test compound in a donor well.

Papp is expressed in 10-6 cm/sec.

n=3

The % recovery can be useful in interpreting the Caco-2 data. If the recovery is very low, this may indicate problems with poor solubility, binding of the compound to the test plate materials, metabolism by the Caco-2 cells or accumulation of the compound in the cell monolayer. The % recovery was calculated using the following equation:

% recovery=Cacc×Vacc+Cd×VdCinitial,d×Vd×100,

Vacc – volume of compound solution in acceptor well (1.0 cm3 in the test A → B; 0.3 cm3 in the test B → A),

Vd – volume of compound solution in donor well (0.3 cm3 in the test A → B; 1.0 cm3 in the test B → A),

Cacc – concentration of test compound in acceptor well (μM),

Cinitial,d – initial concentration of test compound in a donor well (μM).

n=3

Sample preparation for dissolution study

Samples preparation for dissolution study were prepared in the requirements of Ph. Eur. regarding dissolution tests. The final concentrations were 0.02 mg/mL for atorvastatin (absorption maximum at λ = 247 nm) and 0.03 mg/mL for lisinopril (absorption maximum at λ = 212 nm).

In vitro dissolution of twelve tablets containing atorvastatin and lisinopril was performed using buffer solutions (pH 1.2; 4.5; 6.8) as the dissolution media at 50 rpm. The dissolution study was carried out in a 900 mL volume of buffer solution at 37 °C (± 0.5) using the paddle method. One mL of sample was withdrawn and replaced with fresh dissolution medium at the time intervals of 5, 15 min. The concentrations of atorvastatin and lisinopril in samples were determined by spectrophotometric method.

Results and discussion

The main parameters that are analyzed in relation to the API for the possibility of the biowaver procedure are solubility and absorption. First of all, it is necessary to establish and discuss the pH-dependent solubility profile of API. A drug substance is considered to be highly soluble if the highest single dose of immediate-release drug is completely dissolved in 250 mL of buffer solutions in the range of pH 1–6.8 at 37 ± 1 °C. However, for confirmation, it is necessary to perform studies in three buffer solutions within this range (at pH 1.2, 4.5 and 6.8) and also additionally at pKa, if its value is in the above pH range. In the procedure, a biowaver based on Biopharmaceutics Classification System (BCS) gives preference to data of complete absorption in humans (Aggelos et al 2019). In this context, the absorption is considered complete if the measured absorption level is ≥ 85%. Complete absorption in most cases is associated with high permeability. Highly soluble drugs with incomplete absorption (class III according to BCS) are entitled to a biowaver procedure based on BCS, provided that certain preconditions regarding the composition of the drug and dissolution in vitro are met. In the process of developing a dosage form, dissolution tests are used as a way to identify influencing factors and can have a decisive influence on the bioavailability of the drug. After determining the composition and development of the production process, dissolution tests are used to control the quality of batches made by process scaling and industrial batches to ensure both reproducibility from batch to batch and that dissolution profiles remain similar to batches used in the main clinical trials. In addition, dissolution tests can in some cases be used to refuse in vivo bioequivalence studies.

Comparative dissolution profiles obtained by spectrophotomectic method of determination of atorvastatin and lisinopril in tablets are shown in Table 7. The drugs were found to obey beers law at the selected wavelength. The overlain spectra of the atorvastatin and lisinopril in methanol were recorded and λmax values of both drugs and isobestic wavelength were noted.

Table 7.
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Comparative dissolution data of atorvastatin and lisinopril in selected brands.

Brand code Medium % dissolved 5 min % dissolved 15 min
Lisinopril (10 mg) (Tablets A) pH 1.2 85.67 88.38
pH 4.5 88.45 91.06
pH 6.8 87.49 92.09
Lisinopril (10 mg) (Tablets B) pH 1.2 85.56 87.87
pH 4.5 87.38 89.18
pH 6.8 87.94 93.48
Lisinopril (10 mg) (Tablets C) pH 1.2 85.56 86.38
pH 4.5 87.85 90.05
pH 6.8 86.82 92.04
Atorvastatin (10 mg) (Tablets A) pH 1.2 85.34 95.26
pH 4.5 85.76 94.94
pH 6.8 86.39 96.82
Atorvastatin (10 mg) (Tablets B) pH 1.2 86.95 93.67
pH 4.5 87.76 94.01
pH 6.8 90.57 94.27
Atorvastatin (10 mg) (Tablets C) pH 1.2 85.76 91.69
pH 4.5 89.19 93.45
pH 6.8 87.63 92.31

In all three dissolution media, the releases of atorvastatin and lisinopril of all dosage forms were more than 85% in 15 min (Table 7). The dissolution profile of all the selected brands was estimated to be within the standard limits and was acceptable. In medium with hydrochloric acid pH 1.2, in the medium of acetate buffer solution with a pH of 4.5 and in the medium phosphate buffer solution with a pH of 6.8 for 15 min more than 85% of the active substance passes into solution, hence the dissolution profiles these drugs in these environments are similar, and the drugs in them are “very quickly soluble”.

Among the in vitro models that make it possible to assess the degree of absorption of API, the most widely used culture of adenocarcinoma cells of the colon – Caco-2.The development of the analytical methodology and its validation is the final stage of both the dissolution study and the Caco-2 test, as well as the biowaver procedure. It plays the most important role in the reliability of the results for all the above procedures and tests.

In our study, optimization and critical evaluation of mobile phase composition, flow rate, and analytical column were important to obtain good resolution of peaks, which in turn affect reproducibility of the method. The resolution of peaks was achieved with Discovery C18, 50 × 2.1 mm, 5 μm column.

Typical multiple reaction monitoring chromatograms of atorvastatin and lisinopril shown in Figs 1, 2. Under these conditions, the peak of vatorvastatin was eluted for about 1.98 min, lisinopril – 1.58 min. The total chromatographic run time was 2.5 min, so the developed analytical method for the determination of atorvastatin and lisinopril to study intestinal permeability in the model of the Caco-2 test was express.

Figure 1. 

Typical multiple reaction monitoring chromatograms of atorvastatin.

A-B permeability data for the test compound of atorvastatin, lisinopril and the three reference compounds are listed in the Table 8. A-B permeability data for all the reference compounds correspond to the literature data (HPA Culture Collections undated), thus validating this study. According to the results presented in Table 8, atorvastatin and lisinopril showed low permeability.

Table 8.
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Permeability coefficient (Papp) of atorvastatin, lisinopril and three reference compounds through the monolayer of Caco-2 cells in the apical-basolateral direction.

Analyte Papp (АB), 10-6 cm/sec
1 2 M m
Propranolol 16.4 16.1 16.2 0.2
Atenolol 0.6 0.7 0.6 0.02
Quinidine 4.2 6.7 5.5 1.8
Lisinopril 0.3 0.2 0.2 0.03
Atorvastatin 0.9 0.8 0.9 0.1

* Abbreviations: M is the arithmetic mean value of the permeability coefficient; m is the standard deviation.
Figure 2. 

Typical multiple reaction monitoring chromatograms of lisinopril.

Recovery data of transport of atorvastatin, lisinopril and the three reference compounds through a monolayer of cells of the Caco-2 are listed in Table 9. The values ​​of mass balance (recovery) of transport of test and control substances through the monolayer of cells of the Caco-2 line (Table 9) indicate that the results of the experiment can be considered reliable.

Table 9.
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Recovery data of transport of atorvastatin, lisinopril and the three reference compounds through a monolayer of cells of the Caco-2.

Analyte % recovery
1 2 M
Propranolol 63 69 66
Atenolol 108 106 107
Quinidine 78 74 76
Lisinopril 95 94 95
Atorvastatin 92 94 93

* Abbreviations: M is the arithmetic mean value of % recovery.

The equivalence of the drugs “Lisinopril”, tablets of 10 mg and “Atorvastatin”, tablets of 10 mg, belongs to class III BCS proven by in vitro studies.

Conclusion

Study of the dissolution kinetics of drugs in solid dosage form with lisinopril and atorvastatin and intestinal permeability to assess their equivalence in vitro were described. Comparative dissolution profiles obtained by spectrophotomectic method of determination of atorvastatin and lisinopril in tablets shows that in all three dissolution media the releases of atorvastatin and lisinopril of all dosage forms were more than 85% in 15 min. The dissolution profile of all the selected brands was estimated to be within the standard limits and was acceptable. To study permeability, method LC-MS/MS was developed. According to the obtained results, atorvastatin and lisinopril showed low permeability. The values ​​of recovery of transport of test and control substances through the monolayer of cells of the Caco-2 line indicate that the results of the experiment can be considered reliable. The equivalence of the drugs “Lisinopril”, tablets of 10 mg and “Atorvastatin”, tablets of 10 mg, belongs to class III BCS proven by in vitro studies.

Acknowledgements

Authors are grateful to the Ministry of Health of Ukraine Fund for providing scholarship for studies related to solutions for development of original combinations of antihypertensive agents, their analysis and standardization (0120U104201).

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