Product and Process Design.

Coordinated by Yihong Qiu ]

Understanding Design and
Development of Modified
Release Solid Oral Dosage Forms
Yihong Qiu and Deliang Zhou

“Product and Process Design” discusses scientific and a robust MR drug product during formulation and
technical principles associated with pharmaceutical process development.
product development useful to practitioners in valida- • Validation and compliance personnel should have
tion and compliance. We intend this column to be a a general understanding of the principles and
useful resource for daily work applications. design process of MR solid oral dosage forms,
Reader comments, questions, and suggestions are and be vigilant of raw material and manufactur-
needed to help us fulfill our objective for this col- ing changes that may impact product quality and
umn. Please send your comments and suggestions manufacturability.
to column coordinator Yihong Qiu at [Link]@
[Link] or to managing editor Susan Haigney at INTRODUCTION
shaigney@[Link]. Modified release (MR) dosage forms are developed
by altering drug absorption or the site of drug release
KEY POINTS in order to achieve predetermined clinical objec-
The following key points are discussed: tives. Possible therapeutic benefits of an MR product
• Oral modified release (MR) dosage forms are include improved efficacy and reduced adverse events,
developed by altering the drug release to achieve increased convenience and patient compliance, opti-
predetermined clinical objectives. mized performance, a greater selectivity of activity, or
• MR solid oral dosage forms include extended new indications (1). According to the US Food and
release (ER) and delayed release (DR). Drug Administration (2), MR solid oral dosage forms
• Matrix, reservoir, and osmotic pumps are the most include extended-release (ER) and delayed-release
common ER delivery systems. Other MR systems (DR) products. A DR dosage form releases a drug (or
include enteric, colonic, pulsatile, and bimodal drugs) at a time other than immediately following
release systems. administration. An ER dosage form is formulated
• Rational design of oral MR systems starts with to make the drug available over an extended period
identifying clinical need, defining the target prod- after ingestion, thus allowing a reduction in dosing
uct profile, performing the feasibility studies, frequency compared to a drug presented as a conven-
selecting, formulating, and testing the appropri- tional dosage form (e.g., a solution or an immediate
ate MR system. release [IR] dosage form). For oral applications, the
• Integrated understanding of drug characteristics, term “extended release” is usually interchangeable
release control mechanism, and the key properties with “sustained release,” “prolonged release,” or “con-
of rate-controlling materials is necessary to design trolled release.”

[
For more Author ABOUT THE AUTHORS
information, Yihong Qiu, Ph.D., is a research fellow and associate director in Global Pharmaceutical Regulatory Affairs
go to CMC, Global pharmaceutical R&D at Abbott Laboratories. He may be reached at [Link]@[Link].
[Link]/bios Deliang Zhou, Ph.D., is a principal pharmaceutical scientist in Oral Drug Products, Manufacturing Science
& Technology at Abbott Laboratories. He may be reached at [Link]@[Link].

gxpandjv [Link] Journal of Validation T echnology [Spring 2011] 23

Product and Process Design.

Figure 1: Examples of oral modified release profiles three decades, significant progresses have been made in
(illustration). the development of theory, modeling, rate-controlling
materials, technology platforms, and processing tech-
100.00 nologies. In addition, the emergence and maturation
90.00 of new materials and aqueous-based polymeric disper-
80.00
sions have made MR dosage forms more amenable to
conventional processing technology.
70.00
% Release

60.00 Extended-Release Systems

50.00 ER1 Various physical and chemical approaches can be used
40.00 ER2 to design oral ER dosage forms that extend drug input in
Bimodal ER1 the gastrointestinal (GI) tract. The majority of modern
30.00
Bimodal ER2
proprietary and nonproprietary ER technologies are
20.00 based on polymeric systems. Most ER products on the
DR
10.00 market fall into one of three categories: matrix, reservoir
Pulsatile
(or membrane controlled), and osmotic systems (see
0 5 10 15 20 25 Table I). Drug release from these ER delivery systems
Time (hr) generally involves one or more of the following mecha-
nisms: drug diffusion, system swelling or erosion and
The objective of modifying oral drug release is to mod- dissolution, or osmotic pressure-induced release. Each
ulate the rate of drug input (i.e., dissolution or absorp- type of system has its advantages and shortcomings
tion) in the intestinal tract to achieve a predefined plasma with respect to the performance, applicability, manufac-
profile. Common modes of drug release include delayed turing, control, development time and cost, and other
release (e.g., using an enteric coating), site-specific or considerations.
timed release (e.g., for colonic delivery), extended release Matrix systems. The drug substance is homoge-
(e.g., zero-order, first order, etc.), or programmed release neously mixed with the rate-controlling material(s)
(e.g., pulsatile, etc.). and other inactive ingredients in a matrix system. Drug
Figure 1 illustrates several examples of MR dissolu- release occurs either by drug diffusion from or erosion
tion profiles. The delivery pattern required for a specific of the system. Based on the characteristics of the rate-
therapeutic agent depends on the understanding of its controlling material, the matrix systems can be divided
clinical pharmacology. For example, many body func- into a hydrophilic systems in which the rate-controlling
tions and diseases follow circadian rhythm (e.g., daily materials are water-soluble or swellable and hydrophobic
fluctuations of hormones and heightened tendency for systems consisting of a water-insoluble inert matrix with
asthmatic episodes). By timing drug release, therapeutic minimum swelling.
plasma concentration can be obtained at an optimal time The matrix system is most widely used for extended
to counter the diurnal nature of certain diseases such as delivery of drug substances because of its effectiveness
angina, hypertension, asthma, early morning arthritis, and versatility. Matrix systems accommodate both low
and heart attacks at night. Classic examples of utilizing and high drug concentrations, and drugs with a wide
MR delivery that have achieved significant clinical and range of physicochemical properties. Matrix systems
commercial successes include modified release products are cost-effective and generally easier to scale-up and
of nifedipine, methylphenidate, mesalamine, verapamil, manufacture compared with reservoir and osmotic
and diltiazem. Procardia XL is a zero-order release tablet systems. In addition, these types of systems are usu-
of nifedipine that not only reduces dosing frequency from ally manufactured using conventional processes and
three times per day to once per day, but also drastically equipment.
improves its efficacy and safety profiles. Hydrophilic matrix systems. Hydrophilic matrix
This discussion provides an overview of current MR systems are polymer-based drug delivery systems
technologies and a rational approach to the development involving two mechanisms of drug release: Fickian
of modified-release solid oral dosage forms. diffusional and relaxational release. The primary
rate-controlling materials are polymers that hydrate
COMMON MODIFIED-RELEASE SYSTEMS and swell rapidly in water and form a gel layer on the
Oral MR drug delivery technology has been used to surface of the system. Diffusion across the viscous
develop new products for many years. Over the past gel layer is not the only drug release pathway as ero-
24 Journal of Validation T echnology [Spring 2011] iv [Link]
 Coordinated by Yihong Qiu.

Table I: Common oral-extended release system.

ER system Sub-category General features
Matrix Hydrophilic Drug dispersed in a hydrophilic matrix. Drug release by diffusion and/or erosion.
Hydrophobic Drug dispersed in a hydrophobic matrix. Drug release mainly by diffusion.
Reservoir Single or multiple unit Soluble drug enclosed by an insoluble membrane. Drug release by diffusion
across the membrane. Multiple-unit system preferred for minimized risk of
dose-dumping.
Osmotic One-chamber Drug and osmotic agents reside in the same compartment. Drug release by
osmotic pressure. Limited to more soluble drugs.
Two-chamber Drug and osmotic agents reside in separate compartments. Drug release by
osmotic pressure developed in the osmotic compartment. Suitable for drugs
with low and high solubility.

sion of the matrix following polymer relaxation or core containing solid drug surrounded by an insoluble
dissolution also contributes to the overall release. In film or membrane. A porous membrane is created
addition, diffusional release is influenced by changes by incorporating soluble or leachable additives (e.g.,
in the diffusion path length due to polymer erosion. a water-soluble polymer, plasticizer, etc.), offering
The relative contribution of each component to total a predetermined resistance to drug diffusion upon
release is primarily determined by the properties of contact with aqueous medium. The drug release rate
a given drug and matrix composition. is a function of drug’s solubility, film thickness, and
Hydrophobic matrix systems. Hydrophobic matrix sys- characteristics of both the film and the additives (pore
tems were the earliest oral ER platform for medicinal use. formers). For a specific drug and formulation, the
A well-known example is Premarin tablets, which have release rate remains unchanged (i.e., zero-order) before
been commercially available since 1942. In a hydropho- solid drug is completely dissolved in the core.
bic inert matrix system, the drug is dispersed throughout The preferred reservoir system normally consists of
the matrix that involves an essentially negligible increase many coated units such as beads, pellets, and mini-
of the device surface or change in dimension during drug tablets. Unlike a single-unit tablet, the number of
release. In most cases, drug release involves ingression of particulates of a reservoir system is often sufficient to
water followed by dissolution and diffusion of the drug minimize or eliminate the impact of any individual
through the matrix. coating defect. An additional important feature of a
In a diffusion-controlled matrix system, the path- multiunit system is that tailored drug release can be
way for drug diffusion increases and releasing sur- readily obtained by combining subunits with different
face decreases with time as the diffusion front moves release characteristics. The multiunit system is also
inward, resulting in decreasing release rate over time adaptable to varying dose strengths without the need
(i.e., drug release is nonlinear). In addition, release of changing the formulation. This feature is highly
rate of a drug with pH-dependent solubility typically desirable during clinical trials of the new drug candi-
varies with pH of the release medium. To overcome dates where dose levels are frequently adjusted based
these shortcomings, various designs have been reported on study outcome.
that effectively alter the drug release behavior from the Similar to matrix systems, drug release from a reservoir
matrix systems (1). For example, non-uniform drug system usually varies with pH unless the solubility of the
loading was used to offset the decrease in release rate active is pH-independent. To achieve pH-independent
by increasing the diffusional driving force over time. release, buffering agents are incorporated to control pH
Geometry factors including cone shape, biconcave, in order to maintain constant drug concentration in
hemisphere with cavity, etc. were utilized to com- the core.
pensate the decreasing release rate by increasing drug Osmotic pump systems. An osmotic pump is
release surface over time. pH-independent drug release similar to a reservoir device in that it consists of a drug-
has been obtained by incorporating pH modifiers (e.g., containing core enclosed by an insoluble membrane.
salts and ionic polymers). The difference is that the device has an orifice for drug
Reservoir systems. A reservoir system is normal- release, and its core also contains an osmotic agent that
ly utilized to control the release rate of water-soluble acts to imbibe water from the surrounding medium via
active agents. A typical reservoir system consists of a a semi-permeable membrane. Such a device, known as
gxpandjv [Link] Journal of Validation T echnology [Spring 2011] 25
Product and Process Design.

the elementary osmotic pump (EOP), was first described examples of the non-monotonic and multi-cargo delivery
by Theeuwes and Higuchi in 1975 (3). Drug release patterns include delayed drug delivery in different seg-
from the device is controlled by water influx across the ments of intestines, pulsatile delivery, biphasic delivery,
semi-permeable membrane. The drug is forced out of and associated combinations. These drug release profiles
the orifice by the osmotic pressure generated within the can generally be obtained through combining different
device. The size of the orifice is designed to minimize immediate-release, delayed-release, and extended-release
diffusion and prevent the build-up of a hydrostatic pres- formulation approaches.
sure head that can change the osmotic pressure and the Enteric-release systems. Enteric release is intended
volume of the device. to delay the release of an active drug until the dosage
In developing oral products, two types of osmotic unit has passed through the stomach. The delayed libera-
pump systems have been utilized. These are a one- tion of oral drugs has been achieved through a range of
chamber EOP system and a two-chamber system (e.g., formulation approaches, including single- or multiple-
Push-Pull). In general, an EOP system is only feasible unit systems coated with pH-sensitive films. The earliest
for molecules with a narrow range of solubility (e.g., physicochemical approach to delaying drug release is
approximately 50-300 mg/mL) to achieve zero-order by applying enteric coating to dosage forms as a barrier.
and complete release. The two-chamber device was Materials used for enteric coating prevent drug release in
designed mainly to accommodate less soluble drug or the stomach because they are typically acidic polymers
higher drug loading. It consists of a bilayer tablet with one that are insoluble and stable at acidic pH. The coatings
push layer containing a highly swellable polymer and a dissolve rapidly when the dosage forms reach the small
drug-containing layer. In the GI tract, water is imbibed intestine. Drugs that are irritating to the stomach (e.g.,
through the semi-permeable membrane into both layers aspirin) can be coated with an enteric film that will only
by the osmotic excipients. As both the drug and push dissolve in the small intestine. Enteric coating is also used
layers hydrate, a drug suspension or solution is formed to prevent certain acid-labile drugs (e.g., proton pump
in situ and the push layer begins to expand as a result of inhibitors) from degrading in the acidic environment.
the hydration and swelling of the hydrophilic polymers. Common enteric dosage forms include coated tablets or
Drug release begins when the volumetric expansion of capsules, and coated multi-particulates in a capsule or
the push layer starts to “push” the active in the drug layer compressed into a disintegrating tablet.
through the orifice on the drug layer side. Because rate- Colonic-release systems. Targeted drug release in
control resides within the rate-controlling membrane, the colon is known to offer therapeutic advantages for
drug release is essentially insensitive to environmental certain drugs, such as more effective treatment for local
effects, such as pH, agitation, and type of apparatus. disorders of the colon (e.g., ulcerative colitis and Crohn’s
In summary, classic osmotic pump systems offer disease) with reduced incidence of systemic side effects.
zero-order release profiles that are independent of the Colonic delivery systems are delayed release dosage
drug properties and release environment in most cases. forms that are designed to provide either an immediate
However, fabrication of this type of system often requires or sustained drug release in the large intestine. One of
specialized equipment with complex processes. This is the examples is colonic delivery of mesalazine for the
particularly true with the two-chamber systems, which treatment of inflammatory bowel disease. For drugs that
often translates into higher cost, longer development are well absorbed throughout GI tract, sustained delivery
time, and larger numbers of formulation and processing in the colon has also been utilized in the treatment of
variables to define and control. Additional drawbacks nocturnal asthma or angina (e.g., cardiovascular chro-
include the solvent process required for semi-permeable notherapeutics products Adalat CC and Verelan PM).
membrane coating, sensitivity of the drug release to for- For optimal colonic delivery, the active needs to be pro-
mulation and process variables, and delayed onset of tected from the environment of the upper GI tract before
drug release. it reaches the large intestine. Based on the considerations
of the unique colonic environment (e.g., pH, pressure,
Other Types of Oral or microflora), various strategies and approaches have
Modified-Release Systems been investigated for colon-specific drug delivery. These
With the improved understanding of active substances include coated delivery systems using pH-sensitive or
and clinical pharmacology, various delivery profiles slow-eroding polymers, swelling or osmotic controlled
such as those illustrated in Figure 1 are often required system for timed release, and carriers degraded specifical-
for effective and improved clinical therapy. Common ly by colonic bacteria. Among these approaches, coated
26 Journal of Validation T echnology [Spring 2011] iv [Link]
 Coordinated by Yihong Qiu.

systems that utilize the transit time and pH differential in As with pulsatile-delivery systems, biphasic-release
the GI tract have been utilized in commercial products. profiles are often achieved by combining different for-
Pulsatile-release systems. Pulsatile delivery usu- mulation approaches, such as single- or multiple-unit
ally refers to immediate release of the entire dose in two immediate release, delayed-release, and extended-release
or more portions separated by predetermined lag times. systems based on coating, matrix, and osmotic pump
In particular, oral pulsatile drug release pertains to the technologies. Among common designs that have been
burst delivery of drugs following a programmed pat- applied are mixing dosage unites with varying release
tern from the time of oral administration. For example, rates, using layered tablets or multi-walled coatings,
Ritalin LA capsule is a pulsatile delivery product that compression-coated tablets with a slow eroding outer
provides immediate release of 50% of the total dose layer, and combinations of delayed-release coatings with
upon oral ingestion followed by a burst release of the osmotic pumps. For example, Cardizem CD consists of
remaining drug after four hours. In the field of modified a rapid-release bead and an extended-release bead pro-
release, these types of non-monotonic and multi-cargo ducing a unique stair-step release profile. Adalat CC is a
release profiles have been proven to offer clinical ben- compression-coated matrix tablet that provides zero-order
efits in optimizing chronotherapy, mimicking natural sustained release followed by a delayed burst release.
patterns of endogenous secretion or multiple dosing Lodotra also uses press-coated tablets (GeoClock) that
regimen, and providing optimal therapy for tolerance- provide rapid release of prednisone about four hours after
inducing drugs where constant levels lead to receptor administration at bedtime for a more effective treatment
down-regulation (i.e., acute tolerance). Pulsatile-release of the morning symptoms of rheumatoid arthritis (10).
systems have received increasing interest in new product
development. COMMON
A variety of pulsatile release systems have been inves- RATE-CONTROLLING MATERIALS
tigated and successfully applied in commercial products. Polymers are most widely employed in various MR
The fundamental system design is based on the combi- systems to provide modulation of drug release. Many
nation single or multiple immediate-release units with choices of polymers are available for hydrophilic matrix
delayed release systems. The delayed release component systems. Among them are cellulose derivatives such as
in pulsatile delivery systems includes site-specific systems hydroxypropyl methylcellulose (HPMC), synthetic poly-
in which the drug is released at the desired site within mer such as poly(ethylene oxide) and poly(methacrylic
the intestinal tract, or time-controlled devices in which acid) of varying degree of cross-linking, and natural
the drug is released after a predefined time lag. Recent polymers such as xantham gum and alginate. Some of
literature reviews have provided detailed information these polymers such as alginate and poly(methacrylic
on design rationale, strategies and various single- and acid) are polyelectrolytes in nature, thus exhibiting cer-
multiple-unit oral pulsatile delivery systems, including tain unique release-modifying properties.
Pulsincap, Pulsys, and PORT technologies (4,5). Materials for hydrophobic matrix systems are more
Bimodal-release systems. Bimodal or biphasic limited. Fatty acids and their various glycerol esters or
delivery profiles have also been frequently used among other wax-like materials have been used previously.
non-monotonic extended release patterns. The usual Insoluble polymers such as Eudragit RL, RS, ethyl cel-
rationale for such designs includes providing rapid onset lulose, cellulose acetate, and other cellulose esters may
of action by adding an immediate release component be also used.
to an extended release dosage form, optimizing dosing Water-insoluble polymers with or without pore form-
schedules for chronotherapeutic drugs by incorporating ers are often used in the membrane coating of reservoir
a delayed-release component in an extended-release systems. Ethylcellulose, polyvinylacetate, and acrylic
dosage form, generating fluctuations of plasma levels to copolymers (i.e., Eudragit RL 30D, RS 30D, NE 30D)
avoid or attenuate the development of acute tolerance, have been used in these applications.
and overcoming the problems associated with non-linear Cellulose acetate is the most commonly used in semi-
pharmacokinetics and extensive first-pass metabolism, permeable membrane coating of an osmotic pump.
resulting in reduced bioavailability or altered drug or Other cellulose derivatives such as ethyl cellulose and
metabolite ratios (6-9). Since the 1980s, many marketed cellulose butyrate have also been used. Sodium chlo-
products with biphasic drug release have been developed ride, highly swellable poly(ethylene oxide), and other
for various drugs, including verapamil, diltiazem, nife- polymers (e.g. poloxamer) are often used as the osmotic,
dipine, and methylphenidate. agent, swelling, and flux enhancer, respectively.
gxpandjv [Link] Journal of Validation T echnology [Spring 2011] 27
Product and Process Design.

Materials used in delayed release are enteric polymers These designs overcame the acutely acquired tolerance
that dissolve at higher pHs. Depending on drug prop- due to the constant level of drug exposure associated
erties and design objectives (e.g., the extent of release with Ritalin SR, the extended release version of Ritalin.
delay), different polymers or different polymer con- This example and above discussed ER nifedipine show
centrations may be used. For example, Eudragit L 55 that a positive or negative clinical outcome may be ren-
consisting of random copolymer of ethyl methacrylate dered by constant exposure of a drug depending on the
and methacrylic acid at ~ 1:1 ratio is soluble at pH > 5.5. relationship between the kinetics of drug effects and the
Eudragit L 100, a copolymer of methyl methacrylate pattern and timing of drug input. The design of release
and methacrylic acid at ~1:1 ratio, is soluble at pH > 6. characteristics for an MR product should be based on
Eudragit S (100) made of the same monomers but with the optimal drug concentration-time profile defined by
more insoluble component (2:1) is soluble at pH > 7. understanding of clinical pharmacology.
These polymers may be used alone or in combination
to achieve a predetermined release delay. Feasibility Study
In developing MR dosage forms, feasibility assessment
RATIONAL DESIGN OF is essential to product design and development success.
ORAL-MODIFIED RELEASE SYSTEMS Once the delivery mode and in vivo target product profile
The ability to achieve desired in vitro and in vivo perfor- are defined and pharmacokinetic disposition parameters
mance for a given drug substance is highly dependent are available, the corresponding drug input profile can
upon several important factors. These include dose, physi- be obtained by prospective pharmacokinetic simulation
cochemical, biopharmaceutical, pharmacokinetic, and (e.g., via deconvolution of the target plasma profile).
pharmacodynamic properties of the drug, drug delivery With a known therapeutic window, the required input
technology, and dosage form design. Each drug sub- duration and kinetics can be readily determined by ensur-
stance possesses inherent properties that require specific ing the plasma levels are maintained above the effective
considerations to both the drug and the delivery system. concentration over a dosing interval. Feasibility of the
In designing a MR delivery system, a defined clinical simulated delivery in the GI tract is then evaluated. For
rationale with the characteristics of the drug for fea- example, If a predefined plasma profile of a drug cor-
sibility evaluation must be integrated. An appropriate responds to 16 hours of drug input, the majority of the
MR technology and design formulation, based on an given dose will need to be absorbed in the large intestine
understanding of the drug characteristics, dosage form because of the limited residence time of solid dosage
attributes, and manufacturing considerations, is then forms in the upper GI tract. Understanding absorption
selected. In vitro and in vivo evaluations follow. characteristics of the individual active drug in the lower
GI tract is crucial.
Identifying Clinical Need and The regional absorption characteristics of a compound
Defining the in vivo Target Product Profile in the GI tract and residence time of dosage forms are the
The basic clinical objective for an MR product is to most important parameters in assessing the suitability of
achieve optimal drug treatment via programming drug oral MR delivery (1, 12). Because of significant region-
input to provide advantages in efficacy, safety, and patient al differences in surface area, permeability, secretion,
compliance. According to the regulatory directive issued enzymes, transporters, water, and other factors, drug
by the European Agency for the Evaluation of Medicinal absorption often differs in different segments of the GI
Products (EMEA) (11), development of MR products tract. In general, the transit time of most dosage forms
should be based on a relationship between the pharma- prior to arrival at colon is approximately four to six hours
cological and toxicological response and the systemic depending on type of dosage forms and food intake. This
exposure to the drug or metabolite(s) forms. may become a limiting factor for drugs requiring absorp-
The impact of input rate on the efficacy and safety tion beyond this time frame after dosing (13). For certain
ratio can be illustrated by methylphenidate. To meet drugs, favorable absorption in the large intestine may
the clinical need for a more convenient dosing regimen allow continued drug delivery for up to a total of 20–24
of this controlled drug, several new MR products with hours (14). If drug release is not completed by the time
different release modes were designed and clinically the dosage form passes through the absorption region,
proven to be effective since the mid-1990s. The product a portion of the dose will not be delivered. Hence, it is
designs include pulsatile release and biphasic extended important to define the absorption regions or window
release, which provide fluctuations of plasma levels. of a specific compound in the GI tract.
28 Journal of Validation T echnology [Spring 2011] iv [Link]
 Coordinated by Yihong Qiu.

Techniques used to assess regional absorption charac- For solid MR dosage forms, drug release testing is the
teristics of a compound include in vitro or in-situ models most important among various physical and chemical
and site-specific delivery in animal models and human characterization methods. The United States Pharma-
subjects. Permeation characteristics of drugs in different copeia (USP) drug release test is commonly used for
GI segments can be evaluated through in vitro permeability guiding formulation screening. Factors that often affect
of excised tissues or in-situ perfusion studies using animal the system performance (e.g., drug loading, excipients,
models. Site-specific delivery via indwelling access ports release control mechanism, etc.) need to be considered
in conscious animals (e.g., dog and rat) offers direct com- when choosing appropriate in-vitro test methods. Devel-
parison of drug absorption in jejunum, ileum, and colon opment of in vitro release tests and their relationship with
through concurrent monitoring of plasma levels. These can in vivo performance has been discussed previously (16).
serve as a predictive model for human exposure depend- Following completion of the dosage form design and
ing on the drug properties and absorption mechanism. in vitro testing, in vivo bioavailability study of prototype
Since the early 1990s, gamma scintigraphic studies have formulations is required to identify a formulation with
become one of the commonly used techniques in screen- acceptable in vivo performance for further development.
ing drug candidates for oral MR delivery (15). Regional In certain cases, iteration of studies is necessary to define
differences in absorption can be determined by using or refine a formulation. When designed properly, the
non-invasive delivery devices, such as the Enterion capsule study may also offer an opportunity to explore in vitro-in
of Pharmaceutical Profiles (UK). The radiolabeled capsule vivo relationship (IVIVR) or correlation (IVIVC) to aid
loaded with a drug solution or powder can be tracked via product development.
gamma scintigraphy and externally activated to release
the drug when it reaches a certain location in the GI tract. FORMULATION AND
In summary, it is essential to take into consideration the PROCESS DEVELOPMENT
drug’s physicochemical and biopharmaceutical properties, The usual options of MR solid dosage forms are single-
the required dose, physiological and biological constraints, unit tablets, multi-unit beads or mini-tablets in capsules,
and disposition kinetics in assess technical feasibility. and multi-particulates for reconstitution or sprinkle
administration. These are manufactured using essen-
Designing and Testing MR Dosage Form tially the same processes as used for the IR dosage forms.
Once feasibility is confirmed, an appropriate MR tech- Table II lists common dosage forms for different types
nology and in vitro test method to design and evaluate of MR systems.
prototype formulations are selected. This decision should The general aspects of these dosage forms, process
be primarily based on drug properties, dose, desired development, and in-process controls have been dis-
release or absorption kinetics, and clinical and commer- cussed extensively in the literature. In general, processes
cial needs. Additional practical considerations include for tablet manufacture include direct compression, wet
development time and cost and commercial production granulation, dry granulation, and melt granulation
factors (e.g., process, equipment, facility, manufactur- or thermoplastic pelletizing (e.g., high shear, melt-
ability, robustness, cost, capacity, and environment). extrusion, spray-congealing). Processes for producing
In selecting an MR system that matches development spherical beads encompass extrusion-spheronization,
needs, dose and solubility of the active are often the most drug layering of non-pareil seeds, spray-granulation or
important factors to consider because both variables spray-drying, and spray-congealing. Conventional com-
impact the release mechanism and processing behaviors. pression processes are also used to prepare mini-tablets
There is generally no technology that is one-size-fits-all. using either small tooling or multi-head tooling depend-
From an enablement point of view, different MR sys- ing on the tablet size and throughput considerations.
tems can be equally effective in achieving the delivery MR coating of tablets or beads is most often carried out
objective when drug properties and dose are desirable. in pan coater or fluid-bed depending on the nature of
For example, similar MR performance of verapamil, the coating substrate (e.g., size, tensile strength, etc.).
theophylline, and methylphenidate have been obtained Compression coating (tablet-in-tablet) requires a special
using matrix, reservoir, or osmotic pump technologies. compression machine. In most cases, use of conven-
However, depending on dose and solubility, one type tional manufacturing processes and equipment is highly
of delivery system may become more or less suitable for preferred. When a more complex process is required
meeting a particular delivery need. (e.g., multi-layered tablets, compression coating, mixed
In developing an MR dosage form, in vitro assessment beads, or mini-tablets), emphasis should be placed on
of its attributes is essential prior to testing in humans. increased process and product understanding throughout
gxpandjv [Link] Journal of Validation T echnology [Spring 2011] 29
Product and Process Design.

Table II: Common dosage forms of different modified- cal modification of polymers leads to an added layer of
release systems. potential differences in functionality (e.g., hydroxypropyl
MR systems Dosage form methycellulose). Typically compendial monographs are
Matrix ER Single- or multi-layer tablet
very general in defining the chemical structures of poly-
Multi-units in capsule mers, allowing for a wide range of specification values. As
Compression coated tablet a result, the same compendial grade of materials from dif-
Multi-particulates for reconstitution or ferent manufacturers can have different chemical proper-
sprinkle ties that may influence its performance in a specific MR
Reservoir ER Multi-units in capsule system. In many cases, significant variability also exists
Tablet between different lots from the same vendor. Polymer
Multi-particulates for reconstitution or variability and its potential impact on formulation and
sprinkle processing need to be understood during product and
Osmotic ER Single- or multi-layer tablet or process development. In general, to better control mate-
capsule rial variability, it is usually preferred to select a synthetic
Multi-units in capsule
or semi-synthetic polymer (e.g., HPMC) over a natural
Delayed release Tablet polymer (e.g., alginate) because the chemistry and prop-
Multi-units in capsule erties of the natural polymers are often influenced by a
Compression coated tablet
number of factors that are difficult to control.
Multi-particulates for reconstitution or
sprinkle
Pulsatile Release Multi-units in capsule
IMPLICATIONS OF UNDERSTANDING
Layered tablet MODIFIED-RELEASE PRODUCTS IN
Compression coated tablet VALIDATION AND COMPLIANCE
Multi-particulates for reconstitution or Validation and compliance personnel should have a gen-
sprinkle eral understanding of the principles and design process
of modified-release solid oral dosage forms. Specifically,
the development lifecycle to ensure successful develop- they should be very aware of differences and similarities
ment from small to commercial scale. Compared to the among different types of MR products. As with IR dos-
IR counterpart, a higher standard is usually required to age forms, attention should be directed toward drugs
ensure rate-modifying function of the MR product. For and excipients that may interact with each other and
example, tighter or additional control of rate-controlling with manufacturing processes, and processes that may
materials, or uniformity of functional coat for the res- potentially impact product quality and performance.
ervoir and osmotic pump systems, is often necessary to MR products are complex products. Validation and
assure consistent batch-to-batch product performance. compliance personnel must be especially vigilant of raw
In formulation and process development, an integrated material and manufacturing changes that may impact
understanding of the drug release mechanism and key product quality and manufacturability. Special atten-
properties of the rate-controlling materials is important. tion should be paid to the rate-controlling excipients
Release rate control of a MR system is achieved through of which the physicochemical and mechanical proper-
the use of an appropriate functional polymer. Compared ties may vary depending on batch, grade and source,
with small molecules, polymers have inherently higher etc. Changes in material sources or vendors must be
variability in physicochemical properties. It is important thoroughly evaluated. Consultation with development
to understand the structural diversity of these polymers scientists is mandatory whenever any of the above situa-
and potential impact on product performance. tions are encountered. Validation protocols developed in
Polymers may differ in several chemical aspects. response to such changes should require appropriate sam-
Individual polymer molecules have different molecular pling and testing in support of the changes. Knowledge
weight. Each batch usually has different average molecu- of the product and process characteristics must also be
lar weights and distribution, even within the same grade considered in determining appropriate validation testing.
of a polymer. A conventional viscosity test only reflects
the average molecular weight. Most rate-controlling CASE STUDY: MR DOSAGE
polymers are either synthetic or natural copolymers. The FORMS OF METHYLPHENIDATE
exact composition (i.e., ratio between different repeating Methylphenidate (MPH) is an amphetamine-like cen-
units) and their distributions are likely to vary, potentially tral nervous system stimulant commonly prescribed to
affecting their rate-controlling properties. Further chemi- treat attention-deficit/hyperactivity disorder (ADHD)
30 Journal of Validation T echnology [Spring 2011] iv [Link]
 Coordinated by Yihong Qiu.

in children, adolescents, and adults, as well as narco- Figure 2: Plasma concentration-time profile of MPH after a
lepsy. It is soluble, stable, and highly permeable in single dose of MR and IR formulations (19).
the intestinal tract with a short elimination half-life 5
of three-four hours. These favorable properties com- CONCERTA ® 18 mg qd

Mean Plasma Methylphenidate

bined with a low dose make MPH an ideal candidate 4 Methylphenidate 5 mg tid

Concentration (ng/mL)
for oral MR regardless of technologies applied.
The IR product (Ritalin) that has been on the mar- 3

ket since the 1950s is taken two or three times per day.
2
It is inconvenient for repeated administration while
children are at school because MPH is a Schedule II
1
controlled substance. To offer more convenient dos-
ing and control of behavior during the entire school 0
day, several modified-release formulations have been
developed. An early ER product (e.g., Ritalin SR) is a
0 4 8 12 16 20 24 28 32
matrix tablet designed to maintain relatively steady
Time (h)
plasma drug levels after administration. However,
the product was found to be less efficacious due to (a) Concerta
its drug release pattern that led to the development
16
of acute tolerance (17). Further studies demonstrated
Mean Methylphenidate Cp (ng/mL)

that varying rate of drug input would overcome the 14

tolerance observed with monotonic drug release. As 12

a result, a new generation of once-daily MR products 10
was developed that offers the equivalent efficacy of 8
repeated administrations of IR MPH by altering the
6
drug’s input profile. Successful commercial products
4
(18) include ER products generating biphasic release
profiles for a rapid onset of action and a prolonged 2

duration of action (Metadate CD capsules consisting 0

0 1 2 3 4 5 6 7 8 9
of 30% IR and 70% coated ER beads and Concerta
Time after closing (h)
tablets consisting of an ER osmotic pump coated with
IR component [Figure 2a, 2b]) and Pulsatile release 1 X 10mg IR at 0 and 4 h (n = 21)
products that better mimic PK performance of stan- 1 X 20 mg MRTADATE CD (n = 12)
dard schedules of IR product (Ritalin LA capsules 2 X 20 mg MRTADATE CD (n = 9-10)

consisting of 50% IR and 50% DR beads that provide

IR release 4h later [Figure 2c]), This case study shows (b) Metadate CD
that understanding drug properties is critical to the
design of clinically efficacious MR products, and all 20
Mean dI-methylphenidate plasma levels (ng/mL)

three types of technologies are equally effective in Ritalin LA ® : 40 mg q.d. (N=17)

achieving a range of in vivo delivery performance when
15 Ritalin ® : 20 mg q.i.d. (N =16)
the molecule exhibits desirable characteristics suitable
for development of MR dosage forms.
10
SUMMARY
The key elements of designing MR solid oral dosage
forms include understanding the drug substance and 5
defining the clinical rationale. The success of design-
ing a commercially viable MR product depends on the
basic properties of the drug candidate, rather than on a 0
0 5 10 15 20 25
particular delivery technology. Most oral MR delivery
Time (h)
needs can be met using three types of mature delivery
technologies (i.e., matrix, reservoir, and osmotic pump (c) Ritalin LA
systems). Design and development of the manufactur-
gxpandjv [Link] Journal of Validation T echnology [Spring 2011] 31
Product and Process Design.

ing process for a majority of MR products are essentially 12. Steven C. Sutton, “Companion Animal Physiology And
the same as those for IR dosage forms. Therefore, select- Dosage Form Performance,” Advanced Drug Delivery Re-
ing an MR technology for a particular drug should be views 56(10 ): 1383-1398, 2004.
based on considerations of technical feasibility, effec- 13. Bauer, K.H., Lehmann, K., Osterwald, H.P. and Rothgang,
tiveness, practicality, development, and manufacturing G., “Environmental Conditions in the Digestive Tract and
efficiency and cost. their Influence on the Dosage Form,” Coated Pharmaceuti-
cal Dosage Forms, Fundamentals, Manufacturing Techniques,
Biopharmaceutical Aspects, Test Methods and Raw Materials,
REFERENCES Medpharm GmbH Scientific Publishers, Birkenwaldstr,
1. Y. Qiu, “Rational Design Of Oral Modified-Release Drug Stuttgart. pp-126-130, 1998.
Delivery Systems,” Developing Oral Dosage Forms: Pharma- 14. B. Abrahamssona, M. Alpstenb, B. Bakec, U. E. Jonssona,
ceutical Theory and Practice, Edited by Y. Qiu et al., Academic M. Eriksson-Lepkowskaa and A. Larsson, “Drug Absorp-
Press, San Diego, CA. pp-469-96, 2009. tion From Nifedipine Hydrophilic Matrix Extended-Re-
2. FDA, Guidance for Industry: SUPAC-MR: Modified Release Solid lease (ER) Tablet-Comparison With An Osmotic Pump
Oral Dosage Forms Scale-Up and Postapproval Changes: Chem- Tablet And Effect Of Food,” J. Controlled Release 52(3):
istry, Manufacturing, and Controls; In vitro Dissolution Testing 301-310, 1998.
and In vivo Bioequivalence Documentation. US Department of 15. C. G. Wilson and N. Wahsington, “Gamma Scintigraphy
Health and Human Services, Food and Drug Administra- in the Analysis of the Behaviors of Controlled Release Sys-
tion, Center for Drug Evaluation and Research, 1997. tems,” Handbook of Pharmaceutical Controlled Release Tech-
3. Theeuwes F and Higuchi T. US patent 3,916,899, 1975. nology, Edited by D. L. Wise, A. M. Klibanov, R. Langer.
4. Maroni, Alessandra; Zema, Lucia; Cerea, Matteo; Sangalli, A. G. Mikos, N. A. Peppas, D. J. Trantolo, G. E. Wnek and
Maria Edvige, “Oral Pulsatile Drug Delivery Systems,” Ex- M. J. Yaszeski. Marcel Dekker, Inc. New York, NY, Pp551-
pert Opinion on Drug Delivery, 2(5):855-871, 2005. 566, 2000.
5. Arora Shweta, Ali J, Ahuja Alka, Baboota Sanjula, Qureshi, 16. D. Zhou and Y. Qiu, “Understanding Biopharmaceutics
“Pulsatile Drug Delivery Systems: An Approach for Con- Properties for Pharmaceutical Product Development and
trolled Drug Delivery,” J. Indian J. Pharm. Sci.68 (3):95-300, Manufacturing II—Dissolution and In Vitro-In Vivo Cor-
2006. relation,” J. Validation Tech. 16(1): 57-70, 2010.
6. Eichel, Herman J., Massmann; Brent D. Cobb, Jr.; Joseph 17. Pentikis, Helen S; Gonzalez, Mario A, “Effect of Formula-
E., Delayed, sustained-release diltiazem pharmaceutical tion on Methylphenidate Release Patterns: Clinical Impli-
preparation, US Patent 5,529,790. cations,” Am. J. Drug Delivery, 3(1):47-54, 2005.
7. Dennis L. Hendrickson, Dan C. Dimmitt, Mark S. Wil- 18. FDA, Briefing Document. United States Food and Drug
liams, Paul F. Skultety, Michael J. Baltezor. Diltiazem for- Adminstration Advisory Committee Meeting for Pharma-
mulation. US Patent 5,286,497. ceutical Science Clinical Pharmacology. April 13, 2010.
8. Barnwell, Stephen G. Biphasic release formations for lipo- 19. FDA, Briefing Document, US FDA Advisory Committee
philic acids. US Patent 5,391,377. Meeting for Pharmaceutical Science Clinical Pharmacol-
9. Cheung WK, Silber BM, Yacobi A., “Pharmacokinetic Prin- ogy, April 13, 2010. JVT
ciples In The Design Of Immediate-Release Components
In Sustained-Release Formulations With Zero-Order Re- ARTICLE ACRONYM LISTING
lease Characteristics,” J. Pharm. Sci. 80(2):142-8. 1991. DR Delayed Release
10. Buttgereit F, G. Doering, A. Schaeffler, S. Witte, S. Siera- EMEA European Agency for the Evaluation of
kowski, E. Gromnica-Ihle, S. Jeka, K. Krueger, J. Szechin- Medicinal Products
ski and R. Alten, “Efficacy of modified-release versus EOP Elementary Osmotic Pump
standard prednisone to reduce duration of morning stiff- ER Extended Release
ness of the joints in rheumatoid arthritis (CAPRA-1): a FDA US Food and Drug Administration
double-blind, randomized controlled trial,” Lancet. 371: GI Gastrointestinal
205-213, 2008. HPMC Hydroxypropyl Methylcellulose
11. EMEA, Points to Consider on the Clinical Requirements IR Immediate Release
of Modified Release Products Submitted as a Line Ex- MPH Methylphenidate
tension of an Existing Marketing Authorization, Euro- MR Modified Release
pean Agency for the Evaluation of Medicinal Products, USP United States Pharmacopeia
Committee for Proprietary Medicinal Products (CPMP)
­December 2003.

32 Journal of Validation T echnology [Spring 2011] iv [Link]