Marina Levina

People have consumed alcoholic drinks for thousands of years and this tradition continues to occupy an important place in many cultures. According to a survey in 2002,

 7–28% of adults in the UK drink alcohol on five or more days a week. US statistical data indicates that a significant proportion of the American population also routinely consumes alcoholic beverages.

	The UK survey shows that older people drink alcohol more frequently than younger people: 21% of men and 11% of women aged 65 years and over had consumed alcohol every day during the week prior to the survey, compared with only 4% of men and 2% of women aged 16–24 years for the same time period. As the prevalence of chronic conditions increase with age, the elderly also consume more drug prescriptions as a percentage of the population for treating cardiovascular, pain management, arthritis and central nervous system conditions. The elderly are also likely to consume more specialized dosage forms because of the continued trend towards extended release (ER) formulations. 

	These trends make it imperative to understand the impact of alcohol consumption on modified release or ER dosage forms.

	Hydrophilic matrix systems are a popular and widely used approach to extending drug release in tablets. Hypromellose (hydroxypropyl methylcellulose [HPMC]) is the most widely used rate-controlling polymer in these systems because of its safety, availability, global compliance and physicochemical/mechanical characteristics.

	Upon contact with aqueous media, HPMC polymer hydrates quickly to form a protective gel layer on the matrix surface. Soluble drugs are released primarily by diffusion through this gel layer while actives with low solubility are released primarily by gel erosion. Drug release typically occurs through a combination of these two mechanisms.

 Rapid polymer hydration and uniform gel formation are critical to the integrity and subsequent performance of HPMC matrix systems.

	Drug release rate from HPMC ER tablets depends on many factors including:

	Drug release rate may also be significantly affected by the medium parameters to which the matrix is exposed, prior to, or upon ingestion, including pH, electrolytes, surfactants and enzymes.

	Taking into account the impact of dissolution medium on gel formation and, therefore, drug release from HPMC matrices, the influence of hydro-alcoholic media for cases when the dosage may be taken with, shortly before or after an alcoholic drink has been recently investigated in a number of studies.

	Accidental poisoning with ER dosage forms, although infrequent, poses special treatment problems that are often not seen with immediate release medication, as failure of an ER product can subject the body to a toxic drug level. Any unintended release of the total or a significant fraction of the active substance from an ER dosage form during a short period of time is referred to as 'dose dumping'.


	The likelihood of dose dumping for certain ER products when administered with food has been investigated previously,

 and FDA has also issued a report to address the issue.

 studies conducted in the 1980s showed that pharmacokinetics and the release properties of ER dosage forms were not influenced by alcohol.

	Labels warning against the concomitant use of alcohol and products that contain alcohol-interactive (AI) drugs are used where appropriate. For other actives (non-AI) that do not have a pharmacokinetic or pharmacodynamic interaction with alcohol, a warning on the adverse consequence of alcohol consumption caused by the potential for dose dumping may not be present on a product label.

. found that 19% of AI and 26% of non-AI drug users reported concomitant alcohol consumption.

	In 2005, FDA issued an alert to healthcare professionals regarding an alcohol-Palladone (Purdue Pharma, CT, USA) interaction.

 This alert cited an increase in the peak plasma concentration of the drug, hydromorphone, to potentially lethal levels because of the breakdown of the dosage form when ingested with significant amounts of alcohol (240 mL of 4, 20 or 40% ethanol). A pharmacokinetic study of healthy volunteers showed that co-ingestion of a Palladone capsule with 240 mL of 40% alcohol caused an average peak drug concentration that was approximately six times greater than when taken with water. One subject also experienced a 16-fold increase when the capsule was ingested with 40% alcohol compared with water. In a few volunteers, 240 mL of 4% alcohol (equivalent to two thirds of a typical serving of beer) resulted in almost twice the peak drug plasma concentration compared with when the capsule was ingested with water.

	Shortly after the FDA alert, Meyer and Hussain reported an overall lack of attention in pharmaceutical science literature and the regulatory assessment process regarding consumption of alcoholic beverages with certain dosage forms, including ER tablets and capsules.

 FDA has subsequently issued advice to minimize the risk of alcohol-induced dose dumping. Therefore, potential effects on the release characteristics of an active substance by alcohol have to be thoroughly evaluated for currently marketed products and new drug applications that utilize an ER mechanism.

Hydro-alcoholic media and the performance of ER formulations

	Since the FDA alert, there have been a number of reports on the influence of hydro-alcoholic media on the performance of ER systems.

 claimed increased permeability, elasticity and swelling of cellulose acetate (CA): polyethylene glycol (99:1 w/w) semipermeable membranes used for osmotic ER drug delivery in 0–60% ethanol solutions.

 Although a slight increase in drug release from the OROS (ALZA Corp., CA, USA) ER systems was recorded, the CA membrane maintained its functionality and no dose dumping was observed.

 studied the influence of hydro-ethanolic media on the release of mesalamine from Pentasa (Ferring, Switzerland) tablets comprising ethylcellulose coated granules.

 The time required for releasing 50% of the drug (T

) was 120 min and 170 min in the absence and presence of ethanol, respectively. This was explained by the lower solubility of mesalamine in the presence of ethanol.

 studied the influence of hydro-ethanolic media on the dissolution rate of aspirin from HPMC (METHOCEL K4M; Dow Chemical Co., MI, USA) matrix tablets.

 They found that aspirin release increased with increasing alcohol concentration in the dissolution media, correlating with the drug's solubility, but did not result in dose dumping. In 40% ethanol, an initial rapid aspirin dissolution rate was reported that was explained by a slower initial interaction between alcohol and HPMC. Using cloud point study results, the authors indicated that ethanol retarded the hydration of the polymer.

 investigated the influence of hydro-alcoholic media on the swelling properties and drug release from HPMC ER matrices.

 The influence of media composition (0–50% v/v ethanol) on the swelling and erosion properties of HPMC (METHOCEL K100 LV CR, K4M CR and K100M CR) compacts was determined using a modified version of the method described by Tahara 

 It was shown that in water and hydro-alcoholic solutions, all compacts underwent swelling and gelation without any disruption to the matrix integrity. The compact wet weight appeared to be similar in water and aqueous ethanol solutions for the METHOCEL grades studied (Figure 1), but the extent of their relative swelling was found to increase with increasing viscosity of HPMC from 100 cps (K100 LV CR) to 4000 cps (K4M CR).

	No significant difference in compact swelling was observed for METHOCEL K4M CR and K100M CR, which was further supported by the findings of Missaghi

 who reported little effect of hydro-alcoholic media (0–40% v/v ethanol) on the textural and rheological performance of HPMC matrices.

investigated the effect of hydro-alcoholic media on three HPMC ER matrix (12 h release) formulations (metformin HCl 500 mg, felodipine 5 mg and gliclazide 30 mg).

 The manufactured matrices were subjected to 5% or 40% v/v ethanol aqueous solutions for 1 or 12 h. The results were compared with drug release in non-hydro-alcoholic media. The tablets retained their hydrated structural integrity when exposed to 5 and 40% v/v ethanol solutions, respectively, for 12 h without any failure of the matrices resulting in dose dumping.

For felodipine and gliclazide, despite increased solubility in hydro-alcoholic media, drug release profiles remained similar to those in water with 

 values greater than 50, indicating statistical similarity.

	When metformin HCl tablets were exposed to 40% v/v ethanol solution for 12 h, a slower drug release was observed compared with exposure to water (Figure 2). This can be explained by a change in drug solubility in the various media. However, when the metformin HCl matrices were exposed to hydro-alcoholic media for only 1 h, the change in drug release profile was not significant.

	Following the advice from FDA to minimize the risk of alcohol-induced dose-dumping from modified release dosage forms, the effect of hydro-alcoholic media on HPMC matrices was evaluated. None of the published papers reported dose dumping from HPMC ER tablets in hydro-ethanolic media. The results of the studies reviewed here indicate that well-designed, robust HPMC ER matrix formulations are safe in situations when the dosage form is taken with, shortly before or after the consumption of alcohol.

 is Global Technical Manager, Modified Release Technologies, at Colorcon Ltd (UK).

 is Global Technical Director at Colorcon Inc. (PA, USA).

	1. National Statistics, "Living in Britain General Household Survey 2002" (2002). 

	3. M.A. Longer and J.r. Robinson, "Sustained-release drug delivery systems," in A.R. Gennaro, Ed., 

 (Mack Publishing, Easton, PA, USA, 1990) pp 1676–1693.

	5. A.R. Rajabi-Siahboomi and M.P. Jordan, 

	10. J.L. Ford, M.H. Rubinstein and J.E. Hogan,

	13. M.E. Campos-Aldrete and L. Vallafuerte-Robles, 

	14. R Espinoza, E. Hong and L. Villafuerte, 

., "Hydrophilic cellulose derivatives as drug delivery carriers: Influence of substitution type on the properties of compressed matrix tablets," in D. L. Wise, Ed., 

Handbook of Pharmaceutical Controlled Release Technology

 (Marcel Dekker, Inc., New York, NY, USA, 2000) pp 1–30.

	19. P.V. Wilder, M.R. Detaevernier and Y. Michotte, 

	21. K. Mitchell et al., Int. J. Pharm., 66(1–3), 233–242 (1990).

 "Particle swelling and the mechanism of failure of HPMC matrices" at the Proc. 3rd Assoc. UK Academy of Pharmaceutical Sciences Conference (London, UK, 1994).

	23. J.L. Johnson, J. Holinej and M.D. Williams, 

	24. L. Hendeles, P. Wubbena and M. Weinberger, 

Guidance for Industry: Food Effect Bioavailability and Fed Bioequivalance Studies

	30. R.J. Meyer and A.S. Hussain, "Awareness Topic: Mitigating the Risk of Ethanol Induced Dose Dumping from Oral Sustained/Controlled Release Dosage Forms," at FDA's ACPS Meeting (October, 2005).

	32. FDA Alert for Healthcare Professionals - Hydromorphone hydrochloride extended-release capsules (marketed as Palladone), Alcohol-Palladone interaction, (July 2005).

	33. J. Koziara, J. So and N. Agarwal, "The effect of ethanol on semipermeable cellulose acetate-based membranes," at AAPS Annual Meeting and Exposition (San Antonio, TX, USA), 29 October–2 November 2006.

	34. H.Fadda, Y. AlBasarah and A. Basit, "Impairment of modified release formulations by alcohol in dissolution media and influence on drug release," at AAPS Annual Meeting and Exposition (San Antonio, TX, USA), 29 October–2 November 2006.

 "The influence of ethanol on aspirin release from hypromellose matrix tablets," at the British Pharmaceutical Conference & Exhibition (Manchester, UK), 4–6 September 2006.

	36. H. Vuong, M. Levina and A.R. Rajabi-Siahboomi, "The influence of hydro-alcoholic media on hypromellose matrix systems," at AAPS Annual Meeting and Exposition (San Antonio, TX, USA), 29 October–2 November 2006.

	37. K. Tahara, K. Yamamoto and T. Nishihata, 

	39. S. Missaghi, K. Fegely and A.R. Rajabi-Siahboomi, "Evaluation of the Effect of hydro-alcoholic Media on Textural and Rheological Characteristics of Hypromellose Matrices," at CRS Annual Meeting and Exposition, (Long Beach, CA, USA, 7–11 July 2007).

	40. S. Missaghi, K. Fegely and A.R. Rajabi-Siahboomi, "Investigation of the Effect of Hydro-Alcoholic Media on Rheological and Textural Properties of Various Grades of Hypromellose," at AAPS Annual Meeting and Exposition, San Diego, CA, USA, 11–15 November).

	41. M. Levina, H. Vuong and A.R. Rajabi-Siahboomi, 

Articles

Research shows that both drug prescription and alcohol consumption increase within the elderly population. It is, therefore, necessary to fully understand the impact of alcohol consumption on solid oral dosage forms, especially extended release formulations.

The influence of concomitant use of alcoholic beverages on hypromellose matrix tablets

The hydrophilic matrix system continues to be the most popular and widely used strategy to achieve extended drug release. Hypromellose (hydroxypropylmethylcellulose [HPMC]) is typically the polymer of choice for the rate-controlling carrier in these systems. 

Table 1 Three model drugs used in the development of HyperStart. 			

In its simplest form, a hydrophilic matrix is a compressed powder mixture of a drug with a water-swelling viscous polymer. A variety of other excipients may be included in the formulation to aid its tableting properties, as well as to modulate the release rate of the active. Key factors in the popularity of hypromellose matrices are: 			

The ease of manufacture using traditional techniques, such as direct compression and granulation on conventional equipment.  

The ability to achieve reliable and consistent drug release when a robust matrix formulation has been developed.

A large array of drug delivery technologies is available to formulators, but hydrophilic matrices remain the most commonly used oral extended release (ER) systems. These devices are easy to manufacture, robust, flexible and reliable. Various water-soluble or water-swellable polymers with high molecular weight have been used in hydrophilic matrices, such as HPMC, hydroxypropylcellulose (HPC) and polyethylene oxide (PEO). HPMC, however, is by far the most popular polymer in matrix applications because of its safety, availability, global compliance and physicochemical/mechanical characteristics.

HPMC has been widely studied for its applications in hydrophilic matrices.

  It hydrates rapidly on contact with water and forms a gelatinous barrier layer around the wetted tablet. Drug release occurs by diffusion of the active through the gel layer and/or by gradual erosion of the gel, exposing fresh surfaces containing the drug to the dissolution medium.  

Diffusion is the dominant mechanism controlling the release of water-soluble actives, and erosion of the matrix is the dominant mechanism controlling the release of water-insoluble actives. Typically, however, drug release occurs by a combination of these two mechanisms.

The most basic matrix formulation consists of the active, polymer, flow aid and a lubricant. Developing a formula that can produce the exact required release profile is quite challenging. The pharmaceutical scientist is confronted with a large number of variables that can influence the processing of the HPMC ER formulation and drug dissolution.  

The release rate from the matrix is dependent upon factors such as polymer type and level; drug solubility and dose; polymer:drug ratio; filler type and level; polymer:filler ratio; particle size of drug and polymer; porosity and shape of the matrix.

Traditional approaches to new product development rely on a slow iterative process that includes experimental programs to identify desirable formulation ranges. These processes require significant investment in manpower and time. 

A number of model drugs with a range of solubilities and concentrations (may not represent therapeutic doses) have been utilized in the development of HyperStart.

  Here, three examples of the actives are illustrated (Table 1), with water solubilities ranging from freely-soluble through to practically insoluble.  

Fillers are generally used to improve processing of tablet formulations (such as flow, compressibility and bulk) and may have a significant impact on the release profiles from HPMC matrices. In the HyperStart model, four commonly used fillers (lactose monohydrate [soluble], microcrystalline cellulose [insoluble], dicalcium phosphate [inorganic-insoluble] and pregelatinized starch [partly soluble]) were investigated. 

Figure 1 shows nine formulations in a simple decision tree that were used to obtain release profiles for three drug solubility and three dose ranges. The experimental study conducted to develop HyperStart included HPMC (Methocel; The Dow Chemical Company) polymers with various chemistries and viscosity grades, as well as different fillers to achieve release profiles ranging from a few minutes to 24 hours. This design acknowledged the complexity associated with developing these systems, but also provided a wide experimental space for later definition by statistical modelling. 

Figure 1 Initial HPMC decision tree system.			

All powder blends were prepared by a standardized process to minimize any random error introduced through formulation preparation variation. The drug, HPMC, filler and 0.5% w/w flow aid (fumed silica, Aerosil 200; Degussa) were mixed in a Turbula blender (Model T2C, Willy A Bachofen UK Ltd)  for 5 min. Magnesium stearate (0.5% w/w) was then added as a lubricant and the formulation was mixed for a further minute. Tablets were manufactured using an instrumented 10 station rotary tablet press (Piccola; Riva) at 20 rpm and a compression force of 10 kN.  

Drug release was measured in a Sotax dissolution bath using USP Apparatus II (paddles) at 100 rpm with sinkers. The dissolution medium was 1000 mL of purified water at 37.0 °C ± 0.5 °C. A dual beam spectrophotometer (Lambda 25, Perkin Elmer) was utilized for drug detection. 

Table 2 f2 values of release profiles calculated from HyperStart compared with experimental data.			

Predictive modelling and analysis were conducted using the Design of Experiments (DoE) Fusion Pro (S-Matrix Corporation) software package. DoE assisted in understanding complex interactions and relationships that may exist between the raw materials in all the tested formulations. With the help of this software, the effects of individual raw materials and the boundaries of operation were explored by progressing in two phases.  

Initially, a screening study primarily examined the boundaries of useful inclusion levels for the raw materials, followed by a second phase of optimization. Both phases involved generating and testing several formulations, and the results from these experiments were recorded as dependant variables (i.e., responses). These were interpreted by the software to produce predictive formulations based on desired parameters in the final product.  

In some cases, where particular variables could impact the release rate of specific actives, corrective algorithms were applied to the formulations that did not perform exactly as expected. The representative drug release profiles were then fed back into the model for fine-tuning of the system where necessary. 

After conducting the required experiments, numerous relationships between formulation parameters and the release profiles of the actives were established, that is: 			

Drug solubility and drug:polymer ratio are the most important factors.  

Release rate is faster with more soluble drugs compared with low solubility drugs. 

Release is faster with a soluble filler compared with an insoluble excipient. 

Based on these relationships, a mathematical model was produced that would offer a HPMC ER formulation with the desired drug release, taking into account solubility and the dose of the active. This model is a valuable tool that can accelerate the hydrophilic matrix development cycle and reduce the time required for a product to reach the market. 

The model was validated by comparing predicted drug release with experimental data. Figures 2 and 3 show model validation for formulations with a soluble drug, various amounts of HPMC (10%, 25% and 40% w/w) and either soluble or insoluble filler. 

Figure 2 Model validation for formulations containing soluble drug, soluble filler and various amounts of the polymer (10%, 25% and 40% w/w).			

Predicted drug release profiles were compared with the experimental data using the 

 value between 50 and 100 indicates that the two dissolution profiles are similar. 

For both filler types, it was found that formulations with the higher polymer concentrations (25% and 40% w/w) exhibited significantly better correlation between predicted and experimental drug release profiles compared with tablets containing only 10% w/w HPMC.  

Figure 3 Model validation for formulations containing soluble drug, insoluble filler and various amounts of the polymer (10%, 25% and 40% w/w).			

These results confirmed that the HyperStart model prediction is reliable, particularly for formulations with moderate to high polymer level (25% or 40% w/w). This range is within current understanding of a reliable HPMC ER matrix system. Our practical experience in the development of HPMC drug delivery devices has identified that polymer concentration has a significant effect on the robustness of a given formulation. With polymer inclusion levels greater than 30%, the effects of any small variations in any of the individual raw materials (including the active principal) are suppressed or eliminated. This then ensures more reliable clinical performance.

The following case studies are presented to illustrate the effectiveness of HyperStart in generating robust formulations with desired release profiles for two drugs, a high solubility/high dose and a low solubility/low dose. 

Table 3 HPMC ER formulation of metformin HCl 500 mg recommended by HyperStart.			

Case study 1. Hypromellose matrix with a freely soluble, high dose drug: 500mg metformin HCl.

 Metformin HCl was used as a typical, freely water-soluble, high dose (50% w/w) model active with poor inherent compressibility (Palmer et al, 2005).

  The solubility and dose (500 mg) of the drug were used as the input parameters by HyperStart to suggest a 12 hour extended release matrix formulation (Table 3), with a release profile similar to the marketed reference product Glucophage XR (Bristol-Myers Squibb). 

Microcrystalline cellulose and fumed silica were screened through a 500 μm sieve. All ingredients, with the exception of the magnesium stearate, were then blended in a Turbula mixer for 5 min. Magnesium stearate was then added and the formulation mixed for an additional minute. 

Caplets with a target weight of 1000 mg were manufactured using an instrumented 10 station rotary tablet press (Piccola; Riva), fitted with 7 × 18 mm tooling; at 20 rpm and 28 kN compression force. Tablet mechanical strength was determined using automatic tablet (Dr Schleuniger-Pharmatron) and friability testers (Copley). 

The drug release profile was measured in a United States Pharmacopeia (USP)-compliant dissolution bath (Vankel) using apparatus II (paddle method) at 100 rpm. The dissolution media was 1000 mL of purified water at 37 °C ± 0.5 °C. A dual beam spectrophotometer (Agilent) fitted with 0.01 mm cells was used for detection of metformin HCl at a wavelength of 233 nm. 

The formulation exhibited good powder flow properties resulting in a low tablet weight variation (<1%). Matrices with a high breaking force (20.8 ± 1.5 kp) and low friability (<0.01%) values were produced. These results were similar to the reference product (<1% weight variation, 19.0 ± 0.2 kp breaking force, 0.01% friability). 

The drug release profile from the formulation manufactured was compared with that of Glucophage XR (Figure 4). The calculated 

 value was 70, indicating good similarity between the two formulations. 

Figure 4 Metformin HCl release from the formulation suggested by HyperStart and Glucophage XR tablets (n = 6).			

The metformin HCl HPMC ER formulation generated by HyperStart produced tablets with good physical characteristics and a drug release profile similar to the reference product. This case study demonstrates that HyperStart can be utilized to develop reliable hydrophilic extended release matrix formulations for high dose/high solubility drugs. 			

Case study 2. HPMC matrix with a practically insoluble/low dose drug: 10 mg nifedipine.

 Nifedipine was used as a typical practically water-insoluble, relatively low dose (10 mg) active.

  The solubility and concentration (10% w/w) of the drug was used by HyperStart to suggest an 8 hour extended release matrix formulation (Table 4), with a release profile within pharmacopoeial specifications.

Lactose and Methocel E15 LV were blended in a polyethylene bag for 3 min. The drug was screened through a 420 μm sieve to break up any aggregates, added to the mix and blended for 3 min. Methocel K15M CR was then added and blending continued for a further 3 min. Magnesium stearate and fumed silica were screened through a 150 μm sieve, added to the mixture and blended for a further minute. 

The hydrophilic matrix system continues to be the most popular and widely used strategy to achieve extended drug release. Hypromellose (hydroxypropylmethylcellulose [HPMC]) is typically the polymer of choice for the rate-controlling carrier in these systems.

Application of a modelling system in the formulation of extended release hydrophilic matrices

This article examines the importance of core design and formulation on the quality of a film coated tablet...