Modeling and comparison of dissolution profiles for different brands of albendazole boluses

Abstract

Background

Addressing critical veterinary drugs, especially drugs with solubility problems like albendazole, and their implications for therapeutic efficacy, in-vitro dissolution studies can indeed provide valuable insights into how different brands of albendazole boluses perform under standardized conditions, helping to assess their dissolution profiles and potential bioavailability.

Methods

Six brands of albendazole 300 mg boluses were collected from December 2020 to May 2021 G.C. The laboratory work was conducted from December 2020 to May 2021 in the National Animal Products and Veterinary Drugs and Feed Quality Assessment Centre (APVD-FQAC) laboratories. The collected brands from government veterinary clinics and private veterinary shops were subjected to model independent and dependent parameters. The dissolution test was conducted according to the USP monograph.

Results

The study found that none of the six brands met the requirements of the dissolution test, as their API release was less than 80% within the specified 60-minute timeframe according to USP standards. Model independence indicated that only one brand (Alb002 = 3.72) achieved a difference factor of ≤ 15%. The remaining four brands (4/6) did not meet this criterion. However, the similarity factor (f2) revealed that all five brands (5/6) were comparable to the comparator products, with f2 values of $\:\ge\:$50%. The mean dissolution time results confirmed that three brands (3/6) had the highest dissolution rate and the fastest onset of action. The model-dependent kinetics indicated that the Weibull and Korsemeyer-Peppas models were the best fit for the release of drug substances.

Conclusion

The study highlights issues with albendazole boluses’ quality, highlighting the need for national in-vitro dissolution studies. These recommendations could improve quality control, streamline regulatory frameworks, and offer practical, cost-effective methods for evaluating drug efficacy and safety, ensuring veterinary pharmaceuticals meet safety and efficacy standards.

Introduction

Poverty and malnutrition are significant challenges in many African countries. The interplay of poverty and malnutrition creates a cycle that is difficult to break [1]. Agriculture remains the primary driving force behind the economy of sub-Saharan Africa (SSA) [2]. Livestock in the agricultural sector has a significant impact on the daily social life of African countries [3]. The African livestock sector contributes about 30–80% to its Agricultural Gross Domestic Product. From the world’s total, around 85% of livestock keepers are found in SSA countries. Although it produces only 2.8% of the world’s meat and milk outputs, SSA contributes more than 14% of the world’s livestock resources [4].

While Ethiopia has a vast livestock population, its efficiency and productivity are significantly hindered by several factors, such as prevalent diseases, inadequate nutrition and husbandry practices, and insufficient veterinary services [5]. Grazing livestock globally, including those in Ethiopia, face significant risks from parasitic diseases, particularly helminths (worms). These parasites lead to both clinical and subclinical diseases, reducing productivity through various mechanisms [6]. To combat the widespread issue of helminthiasis in livestock farming, anti-parasitic medications, specifically broad-spectrum anthelmintic drugs, are commonly utilized. These medications are essential tools in managing and controlling helminth infections [7].

Albendazole bolus, a broad-spectrum anthelmintic, is widely used in Ethiopia to control and treat helminth infections in livestock. Its extensive use is due to its effectiveness against a wide range of internal parasites, including nematodes, cestodes, and some trematodes [8, 9]. Albendazole is a benzimidazole anthelmintic drug widely used for treating various worm infestations. It was discovered at the SmithKline Animal Health Laboratories in 1972 and has since become a critical drug in managing parasitic infections. Albendazole broad-spectrum activity makes it effective against numerous parasitic worms, contributing significantly to both human and veterinary medicine [10]. It is poorly soluble in water and should be taken with a fatty meal to enhance absorption. The chemical structure of the candidate drug was of the drug was attached as Supplementary Fig. 1.

The poor solubility of albendazole indeed necessitates a thorough evaluation of its bioequivalence. Albendazole low aqueous solubility can significantly impact its dissolution rate, which in turn affects its absorption during gastrointestinal transit. This can lead to variability in therapeutic outcomes, making it essential to ensure that generic formulations are bioequivalent to the reference product [11]. Bioequivalence (BE) studies are scientific methods designed to compare different pharmaceutical products containing the same active constituent or different batches of the same veterinary medical products. These comparisons are based on various factors including formulation, pharmacokinetic (PK) properties, pharmacodynamic (PD) properties, and residual profiles in the tissues of treated animals [12]. The primary aim of BE studies is to ensure that different products or batches perform similarly in terms of their safety, efficacy, and quality, thereby ensuring consistent therapeutic outcomes for the end users [12]. For establishment of bioequivalence and therapeutic interchangeability of different brands of albendazole boluses, dissolution profile determination through fit factors (Similarity and different factors) and model dependent pharmacokinetics parameters are critical.

The biopharmaceutics classification system was embarked to forecast the oral absorption of pharmaceutical compounds intended for human use [13]. The veterinary pharmaceutical landscape currently lacks a standardized Biopharmaceutical Classification System (BCS) akin to the one used in human pharmaceuticals. The BCS for human drugs is a scientific framework for classifying drugs based on their aqueous solubility and intestinal permeability, helping to predict oral absorption. However, the absence of a similar system for veterinary pharmaceuticals means there isn’t a universally accepted method to predict oral absorption in animals by evaluating in vitro data on dissolution, solubility, and permeability of veterinary oral dosage formulations [14, 15]. Nevertheless, veterinary drugs could potentially benefit from the application of these principles if reliable data can be obtained. However, certain obstacles need to be addressed before this can occur. Due to variances in anatomy and physiology between animals and humans, it may not be feasible to extrapolate veterinary drug formulations from human ones. Additionally, veterinary drug formulations may vary in terms of size, excipient content, and usage compared to human drug formulations [16]. Therefore, it is crucial to thoroughly examine the utilization of in vitro data on dissolution and permeability for product evaluation and regulatory decisions. This article, along with future scientific presentations, aims to delve into the potential of implementing these principles in veterinary medicine [15].

FDA’s Center for Drug Evaluation and Research (CDER) has incorporated BCS concepts into several guidance documents, including several pertaining to scale-up and post-approval changes, as well as a guidance for the waiver of in vivo bioequivalence study based on in vitro dissolution data [17]. The Center for Drug Evaluation and Research (CDER) often recommends using in vitro dissolution tests as a surrogate for in vivo bioequivalence studies to avoid the use of costly and complex animal models. Specifically, CDER suggests using 900 mL of 0.1 N hydrochloric acid (HCl) as the dissolution medium for these tests. This approach aligns with regulatory guidelines to provide a practical and cost-effective method for assessing the dissolution characteristics of oral dosage forms [18].

The in-vitro dissolution test plays a crucial role in the veterinary biopharmaceutical classification system as a fundamental source of information. It serves as a critical quality control tool that provides insights into the absorption of drugs following oral administration [19]. This test takes into account several factors, including the release of the drug substance from the dosage form, its dissolution in physiological conditions, and its permeability through the gastrointestinal tract [20]. Ultimately, this test is primarily employed to ensure the quality of pharmaceutical products. Scale-up and Post Approval Change (SUPAC) proposes various techniques for comparing dissolution profiles of distinct products [21]. These techniques encompass both model-dependent and model-independent parameters, which are widely utilized [22].

However, no findings have been discovered that demonstrate the determination of dissolution profiles in the veterinary pharmaceutical field using both model independent and model dependent approaches. Model independent parameters play a crucial role in resource limited countries by enabling the use of cost-effective drugs that are therapeutically significant [23]. Currently, the price of branded products surpasses that of generic drugs [24, 25]. Consequently, there is a greater demand for alternative interchangeable generic products in the veterinary pharmaceutical market. In order to establish their therapeutic interchangeability, model-independent approaches (fit factors) were employed on the selected brands of albendazole boluses commonly sold in the North Gondar pharmaceutical market. In this study specifically utilized the three most crucial and commonly employed methods: fit factors, dissolution efficiency (D.E.), and mean dissolution time. Fit factors are quantified through two methods: f1 (the difference factor) and f2 (the similarity factor). To be deemed similar and bioequivalent, f1 should fall within the range of 0–15, while f2 should be within 50–100 [26, 27].

An alternative approach to comparing dissolution profiles involves utilizing model-dependent methods that control the release of drug substances from the formulation based on pharmacokinetics principles [28]. Various pharmaceutical products utilize unique pharmacokinetic pathways due to the diverse manufacturing practices implemented by industrial companies [29, 30]. In this study, the kinetics of drug release from the dosage form were estimated by following various models including zero order, first order, second order, third order, Higuchi-model, Weibull-model, Hixson-Crowell-model, and Korsemeyer-Peppas model.

Research questions

The study aimed to achieve its objectives based on three research questions, such as (1). Are the different sampled albendazole bolus brands interchangeable with the comparator product? (2) Are the rate of dissolution and onset of action the same for the different brands of albendazole boluses sampled? (3) What are the kinetics of drug substances released from the dosage form?

Materials and methods

Study setting, and period

The samples were collected from the selected three sites found in the North Gondar zone, namely Gondar town, Azezo, and Maksegnit. The different brands of albendazole 300 mg boluses were bought from veterinary health care facilities and privately owned veterinary pharmacy shops. Sample collection was performed from October to January 2020 G.C. Laboratory work was conducted from December 2020 to May 2021 in the National Animal Products and Veterinary Drugs (APVD), Feed Quality Assessment Centre (FQAC), and Ethiopian Food and Drug Administration (EFDA) laboratories.

Chemical and reagents

Methanol (B. No. 4549892, Mumbai, India), HPLC grade acetonitrile (B. No. 2189056, Mumbai, India and B. No. D6L012106L, Carlo Erba, France) supplied by Animal Products, Veterinary Drug and Feed Quality Assessment Center (APVD-FQAC). The reagents utilized include, hydrochloric acid 37% (B. No V1N797131N, Carlo Erba, France), sulfuric acid 98% (B. No 7664939, Mumbai India) provided by APVDFQAC.

The chemicals used include ammonium di-Hydrogen Phosphate (B. No 7722-76-1, Mumbai, India), sodium hydroxide (B. No 15530806, Mumbai India) sodium dodecyl sulphate (B. No. 9840973 F, BDH chemicals ltd Poole, England), Sodium dihydrogen orthophosphate (Bulux laboratories Ltd. 121005) supplied by Addis Ababa University (AAU), College of Health Sciences, School of Pharmacy, department of pharmaceutical chemistry and pharmacognosy. The reference standard for albendazole used was albendazole USP RS (Lot No. R110MO, Mexico, with a potency of 99.6%), which was kindly provided by APVD-FQAC.

Instruments

Ultrasonic cleaner (S. No 0083311134PO04, Dahan scientific Co., Ltd, Korea), pH meter (S. No 31092, Biby scientific Ltd. Co., UK), shaker (S. No 100077495220240 V, Germany), vortex mixer (S. No. F202A0173FI, Italy), vacuum pump (S. No. AP0013735, China), UV- VIS spectrophotometer (S. No. 50038, UK), UV-1800 Shimadzu-UVspectrophotometer (S. No. A1145602220 CD, Japan), Whatman^® qualitative filter paper, Grade 1, diameter 125 mm), Sartories analytical balance (S. No. 26504358, Germany), Erweka dissolution tester apparatus (S. No. 22 135658-2217, Germany), beakers, volumetric flasks, conical flasks, measuring cylinders, pipettes, and funnels were used in this study.

Sample collection

Sample collection took place between October and January of the year 2020. The six albendazole boluses were sourced from both government veterinary clinics and private veterinary pharmacy shops across three different locations within the Gondar zones. A total of six different brands of albendazole 300 mg boluses were collected from all the sites. The selection of the six brands was based on their availability at the study site. In Ethiopia, there is a limited availability of veterinary drugs in the pharmaceutical market, with little attention given to this issue. Due to these constraints, the brands were chosen by taking into account their country of origin, as manufacturing practices vary between countries. Initially, in order to ascertain the brand availability at the study site, preliminary information was acquired and sampling method was put into practice. Prescription paper-based and mystery shopping sampling techniques were utilized in accordance with WHO sample collection strategies [31].

The prescription papers were provided by the University of Gondar veterinary clinic. The mystery shoppers were instructed to approach the veterinary pharmacist or veterinarian at the retail outlets and veterinary clinics. They were to inform them that they are travelers who have been using albendazole 300 mg boluses to treat their cattle’s parasitic condition, and they are currently in need of more medication. The general information regarding name of manufacturer, brand names of the drug and coding of the samples, manufacture date, expiry date, batch number, and country of origin included (Table 1).

As a result of the unavailability of the Albendazole innovator product in the Ethiopian pharmaceutical market, the brand Alb001* was chosen as the comparator product. The selection of the comparator product was based on the WHO Guideline on the Selection of Comparator Pharmaceutical Product for Equivalence Assessment of Interchangeable Multisource (Generic) Products [32]. This guideline recommends choosing a product that has received approval in countries associated with the International Council for Harmonization (ICH), and thus, the market leader product was selected as the comparator [32].

Furthermore, the selection of the comparator was also based on the regulatory member and the drug’s release rate. China is a Regulatory Member of ICH regions, and Brand Alb001* released a high amount at 5, 10, 15, 20, 30, 45, and 60 min. Hence, Brand Alb001* was chosen as the comparator product due to the unavailability of the pioneering innovator product of veterinary albendazole bolus in the Ethiopian pharmaceutical market.

Table 1 General information on the collected Albendazole 300 mg boluses in the study

Dissolution profiles comparison test

Standard solution preparation

18.18 mg of albendazole RS was accurately weighed and transferred to a 50-mL volumetric flask. 2 mL of acidified methanol were added and dissolved. Then it was diluted with 0.1 N HCl to volume and mixed. 5 mL of stock solution was transferred to a 200 mL volumetric flask and diluted with 0.1 N NaOH to give a final concentration of 0.00909 µg/ml [33]. Then, the absorbance of the solution was determined at 308 nm and 350 nm using a UV/Visible spectrophotometer.

Calibration curve for albendazole dissolution test method

A stock solution was prepared by dissolving 18.18 mg of Albendazole BP RS in 50 mL of acidified methanol. The seven concentration levels 0.91, 1.82, 3.64, 5.45, 7.27, 9.09, 10.91 µg/mL were then prepared from the stock by diluting 0.5, 1, 2, 3, 4, 5, and 6 mL of the stock solution to 200 mL with 0.1 N NaOH solution. Their absorbances were determined spectrophotometrically. Besides, concentrations of albendazole against absorbance were plotted to obtain the calibration curves.

Dissolution procedure of albendazole 300 mg boluses

The dissolutions of all brands of albendazole were evaluated using a dissolution apparatus type II (paddle) following the United States Pharmacopoeia protocol (USP, 2015a). The dissolution medium (900 mL of 0.1 N HCl) was transferred to the vessels of the dissolution apparatus. The temperature and the spindle rotation speed were set to 37 ± 0.5 °C and 50 rpm for a single time point of 30 min, respectively. This dissolution medium was used because of the higher solubility of albendazole at an acidic pH compared with neutral or basic media. Boluses from each brand were randomly assigned to the six dissolution vessels. Five (5.0) mL samples were withdrawn at predetermined time points (5, 10, 15, 20, 30, 45, and 60 min). To verify, a 30-minute time point was utilized to assess if all albendazole boluses met the dissolution criteria outlined in the United States Pharmacopeia. Meanwhile, a time range of 5–60 min was applied in accordance with the ICH quality standards and the chemometrics rule to evaluate batch-to-batch uniformity and bioavailability across various brands in order to collect data on the dissolution profile of albendazole boluses.

After each withdrawal, an equal volume of 0.1 N HCl medium that had been maintained at the same temperature was replaced in order to maintain the total volume of the medium constant. The samples (5 mL) were immediately filtered using syringe filter and 3 mL (for label claim 300 mg) of the filtered sample solution was quantitatively taken in to 100 mL volumetric flask. It was diluted to volume with 0.1 N NaOH. The absorbance of each sample was determined at 308 and 350 nm using a UV/Visible spectrophotometer. The difference was taken as absorbance value. A 0.1 N sodium hydroxide was used as the blank solution. The quantity in mg of C12H15N3O2S dissolved was calculated by using Eq. (1).

$${\text{\% Content}}\,{\text{of}}\,{\text{Drug}}\,{\text{Release}}=22.5{\text{C}}\left( {\frac{{{\text{Au}}}}{{{\text{As}}}}} \right)$$

(1)

Where;

C is the concentration in mg per ml of USP albendazole RS in the standard solution, AU and AS are the differences in absorbance between 308 and 350 nm obtained from the solution under test and the standard solution respectively [33].

Data analysis and modeling

The coded data were entered, and Analyzed by Microsoft excel version 2016 worksheet. Descriptive statistics were used to summarize the data. The mean and standard deviation. The Microsoft Excel was used for drawing the calibration curve of the working standards as well as plotting the graph of the time-dependent dissolution profiles of the drug.

The model dependent parameters, % dissolution efficiency and mean dissolution time were performed by the KinetDS 3.0 software program. The, Model-independent, and model-dependent approaches were used to compare the in vitro dissolution profiles of the different brands of albendazole 300 mg boluses.

Model independent approaches (fit factors)

To compare the dissolution profiles of Albendazole 300 mg boluses under study, model-independent methods were considered by applying fit factors (F 1 and F 2), Dissolution efficiency (DE) and Mean dissolution time (MDT).

Fit factors

The difference factor (f1) and similarity factor (f2) of all formulations (Alb001 to Alb006) were determined to choose the optimum formulation from the tested brands using Eqs. 2 and 3. Two dissolution profiles were considered similar and bioequivalent, if f1 is between 0 and 15 and f2 is between 50 and 100 [22].

$${\text{f}}1=\{ [\sum\limits_{{t=1}}^{n} {\left| {Rt - Tt} \right|]/\sum\nolimits_{{t=1}}^{n} {\left[ {Rt} \right]} \} \times 100} $$

(2)

$${\text{~f}}2=50{\text{log}}\left\{ {\left[ {\frac{{100}}{{\sqrt {[1+\mathop \sum \nolimits_{{t=1}}^{n} \left\{ {Rt - Tt} \right\}2/n]} }}} \right]} \right\}~~~$$

(3)

Where;

n = is the number of time points, Rt = is the dissolution value of comparator product at time t, Tt = is the dissolution value for the test product.

Dissolution efficiency

Dissolution efficiency is the area under the dissolution curve within a time range (t1 − t2) [34]. DE was calculated by using the following Eq. (4).

$${\text{DE}}=\frac{{\mathop \smallint \nolimits_{{{\text{t}}1}}^{{{\text{t}}2}} {\text{y}}.{\text{dt}}}}{{{\text{y}}100\left( {{\text{t}}2 - {\text{t}}1} \right) \times 100}}$$

(4)

Where;

y = is the percentage dissolved at time t. The integral of the numerator which is the area under the curve was calculated using the following equation.

$${\text{AUC}}=\mathop \sum \limits_{{{\text{i}}=1}}^{{\text{n}}} \left( {{\text{t}}1 - {\text{ti}} - 1} \right)\left( {{\text{yi}} - 1 - {\text{yi}}} \right)/2$$

Where;

t_i = is the i^th time point, and y_i is the % of dissolved product at time t.

Mean dissolution time

In the study, the mean dissolution time (MDT) was considered to determine the drug release rate from the dosage form [35]. MDT helps assess how quickly the active pharmaceutical ingredient (API) is released from the dosage form. This can be critical for understanding the drug’s performance and ensuring consistent therapeutic efficacy [36]. The rate of drug dissolution and onset of action for determining mean dissolution time for albendazole bolus under consideration was calculated using Eq. (5).

$${\text{MDT}}=\sum \left[ {{\text{ti}}.\Delta {\text{Qi}}} \right]/{\text{Q}}\infty $$

(5)

Not: ti, =is an intermediate time of the intervals of sampling time, $\Delta {\text{Qi}}$ is the amount of API dissolved in every interval of t”, ${\text{Q}}\infty$ is the maximum of API dissolved.

Model dependent approaches

A Several mathematical models have been proposed to study dissolution profiles in order to decide the kinetics of drug release [27]. The models were evaluated by selecting a certain parameter based on % cumulative drug releases vs. time taken. To understand Albendazole 300 mg boluses release kinetics, various mathematical models’ dependent approaches were employed, as discussed under Table 2.

Table 2 Mathematical models for comparison of dissolution profiles Albendazole 300 mg boluses in the study

Results and discussion

The calibration curve for dissolution study

In the present context, calibration curves serve the purpose of illustrating the quantitative correlation between the concentration of the target analytes to be assessed and the corresponding absorbance measured [37]. A linear regression equation was Y = 70.287x-0.0169. Where Y is the absorbance and X is the concentration in µg/mL (Supplementary Fig. 2). The response function (calibration curve) showed a strong linear relationship between the concentration of the tested samples and the absorbance values over the concentration range of 0.91–10.91 µg/mL (r2 = 0.9997).

In-vitro dissolution test results

The study, all the six brands failed to meet the dissolution test acceptance criteria mentioned in USP (Table 3). It was revealed that substandard albendazole medications were being distributed in the veterinary pharmaceutical market in Ethiopia. Corresponding results were also documented in Ethiopia, showing that 8.2% of the tested veterinary drug samples did not meet the required quality standards [38].

A study conducted in Nigeria also indicated that four brands of albendazole boluses failed the dissolution test since they could not release albendazole from their respective boluses up to the specified percentage within 60 min [39]. Veterinary manufacturing companies must adhere to good manufacturing practices in order to address the issue of substandard dissolution of veterinary drugs in the pharmaceutical market. This substandard medication has the potential to facilitate the development of antimicrobial drug resistance due to the inadequate active pharmaceutical ingredient (API) used in its production, which fails to meet the minimum standards [40]. Overall, all six brands release their APIs less than 80% within a maximum of 60 min. This result sparked the study to test the interchangeability of the different brands of albendazole bolus in clinical veterinary practice. Apart from that, drugs that have slow dissolution rates and are administered orally can lead to intermittent and insufficient absorption, which ultimately limits their bioavailability [41, 42].

Furthermore, if a substantial portion of the medication fails to dissolve, only a small quantity of the active pharmaceutical ingredient (API) becomes available for absorption into the systemic circulation, thereby failing to achieve the desired therapeutic effect. Conversely, the unabsorbed portion of the drug can cause the associated side effects [43]. The permeation of drugs through the mucosa in the gastrointestinal tract is only possible when the drug is in a dissolved state. The solubility and dissolution rate of the drug play a crucial role in determining its behavior within the body. The initial concepts regarding drug dissolution were introduced by Noyes and Whitney, and further developed by Nernst and Brunner, leading to the formulation of Fick’s law of diffusion [44]. The inadequate aqueous solubility, leading to poor oral bioavailability, has posed a significant challenge in drug research and development. The sluggish dissolution rate, stemming from low solubility, typically translates to diminished bioavailability of orally-administered medications. Consequently, there may be a need for dose escalation until the blood drug concentration aligns with the therapeutic range, potentially resulting in localized toxicity in the gastrointestinal tract. To address this issue, a variety of methods have been devised to improve solubility, dissolution rate, and oral bioavailability. Formulation strategy stands out as a crucial tool in pharmaceutical development, with fundamental approaches for poorly water-soluble compounds including crystal modification, amorphization, and particle size adjustments [45].

Table 3 Dissolution profile result of Albendazole 300 mg Bolus evaluated in the study (n = 7)

In this investigation, the drug release percentages of the six albendazole bolus brands were also evaluated using a time-dependent graphical approach. The dissolution time (x-axis) was plotted against the percentage of drug releases (y-axis) to compare the results (Supplementary Fig. 3). The graphical depiction of time-dependent dissolution profiles for six different albendazole bolus brands, along with their corresponding drug release percentages, was crucial for conveying data on bioavailability and batch consistency [30].

Comparisons of dissolution profile by model independent parameters

In countries with limited resources, including Ethiopia, it is crucial to have information about therapeutically equivalent veterinary drugs that can be interchanged. This is essential to ensure equal access to veterinary services for animal owners, particularly in sub-Saharan African countries where access to veterinary services is challenged [46]. Based on the in-vitro dissolution test, of the six brands examined, only brand Alb002 (f1 = 3.72) meets the acceptance criteria of a difference factor of less than 15% (Table 4). The remaining brands were not interchangeable with the comparator, as the difference factor (f1) was greater than 15%.

The similarity factor (f2) indicated that, evaluated five brands of albendazole 300 mg boluses were interchangeable with the comparator products as the similarity factor was greater than 50%. Depending on the difference factor (f1), the brands of albendazole 300 mg boluses circulated in North Gondar Zone, specifically Gondar town, Azezo, and Maksegnito, haad clinical issues in which the brands were not interchangeable therapeutically. As per the FDA guidelines of 1997, the values of f1 (difference factor ≤ 15%) and this guideline mentioned that the value of difference factors are very sensitive to the number of dissolution time points [22]. It is essential to closely monitor the process of dissolution time points when evaluating the in vitro dissolution profile. In addition to variations and commonalities, the percentage disparity in dissolution effectiveness among the six brands of albendazole 300 mg boluses was assessed and contrasted based on the acceptance threshold for therapeutic interchangeability outlined in the dissolution efficiency guideline (± 10%) [47]. As can be seen in Table 4, brands Al003 (%DE = 3) and Al005 (%DE = 9) were interchangeable as their % dissolution efficiency was less than 10%, while brands Alb002, Alb003, and Alb004 were not interchangeable with the comparator product as their % dissolution efficiency was greater than 10%. The results indicate that the generic albendazole brands differ from the comparator product in terms of their therapeutic aspects.

Moreover, the investigation sought to analyze the rate at which drugs are released and the onset of action of their effects by considering the outcomes of in vitro dissolution tests. Accordingly, the study provided information regarding mean dissolution time of the included brands of albendazole boluses. As can be seen in Table, brands Alb001 (MDT = 1.31) and Alb004 (MDT = 1.31) had the smallest mean dissolution times, followed by brand Alb006 (MDT = 1.54). However, brand Alb003 had the highest mean dissolution time. Therefore, brands Alb001, Alb004, and Alb006 have a higher rate of dissolution and a fast onset of action, while brand Alb003 may be distinguished by prolonged drug release from the dosage form and a longer onset of action. The mean dissolution time (MDT) characterizes the drug substance release from the dosage form and the retarding efficiency of the polymer [48]. A greater mean dissolution time signifies a slower rate of drug release from the dosage form, resulting in a delayed onset of action. Conversely, a lower mean dissolution time indicates a faster rate of drug release from the dosage form, leading to a quicker onset of action [49].

Implication of the interchangeability study

The implication of the comparator study in the current study was for estimating raw material incorporation during formulation can be summarized as follows:

Quality consistency across brands:

The fact that some brands fit both F1 and F2 parameters indicates that these brands are consistent in their dissolution profiles and are likely to follow similar manufacturing practices. This suggests that, under conditions where all brands meet quality specifications, they could be considered interchangeable in clinical practice.

Interchangeability:

When brands meet the F1 and F2 criteria, it implies that their release profiles are similar. If the only deviation observed is in raw material incorporation (rather than formulation or quality specifications), this indicates that these brands could be used interchangeably. This is especially relevant in veterinary practice where different brands of albendazole could be substituted for one another, assuming their quality is assured.

Quality Assurance:

The deviation from quality specifications in all, however, one brand (Alb002) fit F1 and the remaining four brands fit well F2, indicates a potential issue with interchangeably within the brands. This underscores the importance of rigorous quality control and assurance processes. If only some brands meet the quality criteria, it highlights the need for careful selection and validation of products before their clinical use.

Regulatory and clinical practice implications:

The finding that there are interchangeable albendazole brands available in the veterinary pharmaceutical landscape, if their quality is assured, has significant implications. It suggests that while certain brands can be considered interchangeable, the overall quality must be closely monitored to ensure that all products used in practice meet the necessary standards. This could influence regulatory policies and clinical practices related to drug substitution [50].

Need for standardization:

The variability in meeting the F1 and F2 parameters suggests a need for better standardization and quality control in the production of albendazole brands. This could involve stricter adherence to good manufacturing practices and more rigorous testing to ensure that all brands meet the required quality specifications.

In summary, while some albendazole brands could be used interchangeably if they meet quality specifications, the observed deviations highlight the need for enhanced quality control and assurance to ensure consistency and reliability in clinical practice [51].

Table 4 Comparisons of dissolution profile by model independent parameters in the study

Dissolution profile comparison by Model dependent parameters

It is crucial to analyze drug release or dissolution when developing a new solid dosage form. Utilizing mathematical formulae to interpret dissolution or release rates facilitates the quantitative analysis of obtained values. Mathematical modeling plays a key role in enhancing the design of therapeutic devices and provides insights into the effectiveness of different release models [52]. This study provides a comprehensive analysis of the present status of modeling drug dissolution in order to ascertain the process of drug release from dosage forms. It takes into account various pharmacokinetic parameters including zero order, first order, second order, third order, Korsemeyer-Peppas model, Weibull model, Hixson-Crowell model, and Higuchi model [53].

Several mathematical models have been suggested for examining dissolution profiles in order to determine the kinetics of drug release [54]. The models were assessed by considering specific parameters, such as the percentage of cumulative drug releases versus time. In order to realize the drug release kinetics of albendazole boluses, different mathematical models dependent approaches were utilized. The kinetic equation was used to fit all in-vitro release test data. The model that exhibited the highest Correlation Coefficient (r2) [54] and the lowest Akaike Information Criterion (AIC) [55] value was considered the most suitable fit for the release data, following the application of mathematical model-dependent approaches to each unit of the dissolution data. The choice of the mathematical model was based on the fittings results and the derived statistical criteria AIC and R² values [56].

Different kinetic models were observed for the release of contents from the formulation among various brands (Table 5). This variation could be attributed to the fact that the brands were sourced from different manufacturers who employed distinct manufacturing practices and utilized diverse pharmaceutical excipients. The model-dependent approach showed that all of the tested albendazole boluses were best explained by the Weibull curve and the Korsemeyer-Peppas model, with the highest correlation coefficient (R²) and a lower AIC for all the brands tested (bold print indicating the best fits). The presence of Weibull model release kinetics in albendazole bolus samples suggests that the drug adheres to the release patterns associated with matrix-type drug delivery [52]. Additionally, the Korsemeyer-Peppas model indicated that the kinetics release of the albendazole boluses was due to both diffusion and erosion phenomena occurred throughout the course of dissolution study.

The Weibull curve model yielded correlation coefficients and Akaike information criterion values of R2 = 0.9485, AIC = 3.3267, R2 = 0.9224, AIC = 3.7962, R2 = 0.9246, AIC = 3.8241, R2 = 0.9961, AIC = 1.3342, and R2 = 0.9188, AIC = 3.7589 for brands Alb001, Alb002, Alb004, Alb005, and Alb006, respectively (Table 5). On the other hand, the Korsemeyer-Peppas model showed a correlation coefficient of R2 = 0.99492 and an AIC value of 1.8084 for brand Alb003. Hence, it can be affirmed that every brand analyzed in the study presented a distinct release mechanism.

Table 5 Determination of model dependent parameters in the study

Conclusion

The study attempted to assess the in-vitro dissolution profiles of 300 mg Albendazole-Boluses obtained from three drug retail sites, each supplied by a distinct manufacturer. The results showed that the dissolution test was failed for six different brands of albendazole boluses, as they were unable to release the specified percentage of albendazole within 60 min. The fit factors indicated that only one brand met the criteria for a model independent difference factor of ≤ 15%, while the other four brands did not. Furthermore, the similarity factor (f2) demonstrated that all evaluated brands of Albendazole 300 mg boluses were interchangeable with the comparator products, as the similarity factor exceeded 50%. The dissolution efficiency revealed that only two out of the six brands were interchangeable, as their dissolution efficiency was below 10%. Apart, the mean dissolution time indicated that three out of the six brands had the highest rate of dissolution and a rapid onset of action. Apart, the mean dissolution time indicated that three out of the six brands had the highest rate of dissolution and a rapid onset of action. The Weibull- and Korsemeyer-Peppas models were the best fit for the release of drug substance from the formulation.

In veterinary clinical practice, there was concern regarding the low bioavailability of drugs and the issue of therapeutically interchangeable albendazole 300 mg boluses. Therefore, it is essential for professionals, drug manufacturers, and drug regulatory authorities to conduct a comprehensive evaluation of the dissolution profiles of marketed veterinary drugs in order to establish veterinary biopharmaceutical classification systems, and surrogate base of in-vivo biowaiver test.

Limitation and strength of the study

The limitation regarding the number of brands tested affects the generalizability of your findings to the broader Ethiopian pharmaceutical market. Incorporating statistical comparisons like the Dunnett test and ANOVA could provide deeper insights into the differences between brands and their therapeutic interchangeability. It’s notable that none of the brands met the required specifications, underscoring the need for rigorous quality control in veterinary pharmaceuticals. Additionally, while modeling provides valuable insights, it doesn’t guarantee the efficacy of medications, highlighting the complexities involved in ensuring access to effective veterinary products despite price fluctuations.

The current study stands out for its unwavering strength as it marks the pioneering research in the field of veterinary pharmaceuticals. However, no previous study has been undertaken to ascertain the baseline information for the veterinary biopharmaceutical classification system in terms of both model-independent and model-dependent kinetics. The study also gives information regarding the interchangeability of various brands of albendazole 300 mg boluses in veterinary clinical practice.