(T1430-02-11) Alcohol Dose Dumping in Modified Release Formulations: Critical Considerations for Regulatory Guidance(s)

Purpose: Alcohol dose dumping (ADD) in modified release (MR) formulations accelerates drug release with alcohol, posing safety risks and increasing the chance of adverse events [1]. For this study caffeine-containing MR tablets which were previously optimized using polyvinylpyrrolidone (PVP-90; Kollidon^® K90 EVO) and a polyvinyl acetate (PVAc) dispersion (Kollicoat^® SR 30D), along with polyvinylpyrrolidone (PVP-90; Kollidon^® K90 EVO) as a pore former and triethyl citrate as a plasticizer [2]. The stability of the formulation was investigated under accelerated storage conditions for a period of three months (40 °C and 75% relative humidity, RH). Additionally, the study discusses critical risk mitigation strategies and regulatory considerations for addressing the issue of ADD.

Methods: Stability studies: The PVAc coated caffeine tablets were stored at 40 °C/75% RH in a HDPE bottle (induction sealed) with 1 g of desiccant for one month and three months. At each time point, coated tablets were pulled for dissolution testing. Dissolution studies: Dissolution experiments were performed using a Pion MicroFlux^TM dissolution system, following the USP apparatus II method. The experiments were conducted at 50 rpm, a temperature of 37 °C, and 1000 mL of dissolution media. The tests were performed under four different dissolution media conditions: 1) 0.1N HCl; 2) 0.1N HCl with 20% alcohol (v/v); 3) 0.1N HCl with 40% alcohol (v/v); 4) 0.1N HCl with 40% alcohol (v/v) in first two hours, followed by phosphate buffer (pH 6.8) for another 16 hours. Similarity factor (f₂) was calculated based on 18 hr. dissolution profile in respective dissolution media (Figure 1, Table 1). Film strength analysis: The modified release films were characterized using texture analyzer. Briefly, PVAc dispersion was mixed for 30 minutes (magnetic stirrer) with PVP-90 at polymer weight ratio 3:1 with plasticizer, triethyl citrate at 10%. The polymer mixture was cast as a film by pouring onto a plastic liner using a 50-mil cast spacer, and then allowed the films to air dry at 40°C overnight. The film was cut to a 1 x 3 cm size and soaked in 0.1N HCl and 0.1N HCl with 40% alcohol for 2 hours. Then the texture strength of the films was tested on texture analyzer, with a 0.5 mm/minute pulling speed.

Results: The caffeine tablets consisted of microcrystalline cellulose (MCC), PVP-K 90 (25%) and magnesium stearate. Tablets were coated with PVAc/PVP-90 at ~13.2 mg/cm² demonstrated the modified release properties, including upon storing at accelerated conditions up to three months, (Figure 1A). Complete drug dissolution was achieved within 18 h and there was no burst release up to 2 h even in media containing 40% alcohol (Figure 1B). The MR properties were maintained with dissolution similarity factor, f₂ of higher than 60 as suggested by FDA guidance [3] (Table 1). However, European Medicines Agency (EMA) guidance suggests dissolution testing with 20% alcohol but does not specify the dissolution time [4]. In 40% alcoholic media, the amount of API released was ~20% at 2 h indicating no ADD effect. After changing the media to phosphate buffer (pH 6.8), the drug release increased to 100% after 5 h  (Figure 1C). This release rate is much faster than the rate in 0.1N HCl with no alcohol, where the amount of drug release was ~100% after 18 h (Figure 1A). The observed results can be explained by the texture analyzer studies of the modified release film coating. The film strength was characterized by measuring the force to break the film after soaking in dissolution media with/without 40% alcohol (Figure 1D). Films soaked in 0.1N HCl had twice the strength compared to 0.1N HCl with alcohol. Under the alcoholic condition, the film exhibited lower tensile strength and was easier to break due to swelling of MCC. Once the film is compromised, further continuation of dissolution test led to change in mechanism of drug release with ~100 % release in 5 h. This shows that MR tablet, which may meet the guidance requirement set by the FDA (testing in presence of 0-40% alcohol conc for 2h), may still pose a risk of burst release once the alcohol is removed from the test method. This is due to changes in the release mechanism, or properties of the functional coating material used in the tablet formulation.

Conclusion: The caffeine tablets coated with PVAc/PVP-90 maintained the modified release properties and high dissolution similarity after 3 months. Although the formulation complies with ADD regulatory requirement of FDA, the impact of alcohol on the film characteristics compromises its mechanical strength, leading to faster release in non-alcoholic media. This raises concerns about the adequacy of current FDA requirements for preventing ADD. The discrepancies between the ADD requirements of EMA and FDA can pose challenges for formulators. A harmonized recommendation from regulatory agencies is needed to establish a physiologically relevant in vitro methodology for assessing ADD in MR oral products.

References: [1] D’Souza, S.; Mayock S. and Salt A., AAPS Open, 2017, 3:5
[2] Ming Ji, Nitin Kumar Swarnakar, Shanmuka Chalamuri, Kalyan Kathala, Sandip Tiwari, AAPS PharmSci360, 2023, poster M1030-03-21
[3] https://www.fda.gov/media/70936/download.
[4] https://grants.nih.gov/grants/guide/rfa-files/RFA-FD-24-010.html (accessed on 07/08/2024)

Figure 1 A Dissolution results of MR caffeine tablet after three months ACC storage A) in 0.1 HCl; B) in 0.1N HCl with and without 40%(v/v) alcohol; C) i in 0.1N HCl containing 40%(v/v) alcohol for 2 h followed by phosphate buffer (pH 6.8). Inside is the dissolution of caffeine MR tablets in 0.1N HCl; D) Determination of film elongation at break. a) Orange line, PVAc dispersion with PVP-90 film soaked in 0.1N HCl for 2 hours; b) Blue line, PVA c dispersion with PVP 90 film soaked in 0.1N HCl with 40% alcohol for 2 hours. Right up corner is the texture analyzer

Table 1 Dissolution similarity factor F2.
* Note: The reference for the average dissolution profile of the caffeine tablet in 0.1N HCl at T0.1
** storage condition: 40 °C, 75% RH;
*** calculation of F2 for 0.1N HCl was based on 18h dissolution period, whereas for 0.1N HCl with 20% and 40% alcohol, F2 was calculated based on 2h dissolution period.