Pharmaceutical Development and Technology

ISSN: 1083-7450 (Print) 1097-9867 (Online) Journal homepage: http://www.tandfonline.com/loi/iphd20

Formulation design, challenges, and development

considerations for fixed dose combination (FDC) of
oral solid dosage forms

Divyakant Desai, Jennifer Wang, Hong Wen, Xuhong Li & Peter Timmins

To cite this article: Divyakant Desai, Jennifer Wang, Hong Wen, Xuhong Li & Peter Timmins
(2013) Formulation design, challenges, and development considerations for fixed dose combination
(FDC) of oral solid dosage forms, Pharmaceutical Development and Technology, 18:6, 1265-1276,
DOI: 10.3109/10837450.2012.660699

To link to this article: https://doi.org/10.3109/10837450.2012.660699

Published online: 16 Feb 2012.

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Pharmaceutical Development and Technology, 2013; 18(6): 1265–1276
© 2013 Informa Healthcare USA, Inc.
ISSN 1083-7450 print/ISSN 1097-9867 online
DOI: 10.3109/10837450.2012.660699

REVIEW: PHARMACEUTICAL Development Fundamentals

Formulation design, challenges, and development

considerations for fixed dose combination (FDC) of oral
solid dosage forms
Divyakant Desai1, Jennifer Wang1, Hong Wen2, Xuhong Li3, and Peter Timmins4

Drug Product Science and Technology, Bristol-Myers Squibb Co., New Brunswick, NJ, USA, 2Pentian Pharmaceuticals
1

Company, Shanghai, China, 3CDER, FDA, Silver Spring, MD, USA, and 4Drug Product Science and Technology,
Bristol-Myers Squibb, Co., Moreton, Merseyside, UK

Abstract
Fixed dose combination (FDC) products are common in the treatment of hypertension, diabetes, human
immunodeficiency virus, and tuberculosis. They make it possible to combine two or more drug molecules with
different modes of pharmacological actions in a single dosing unit and optimize the treatment. From a patient
perspective, they offer convenience, reduced dosing unit burden, and cost savings. From a clinical perspective, aging
population in developed countries will need multiple medications to treat age related diseases and co-morbidities.
FDC products simplify dosing regimen and enhance patient compliance. As outlined in the article, the number of
FDC products has grown over the years and the trend is likely to continue. This review article gives an overview to
pharmaceutical scientists about recent trends in the formulation development of the FDC products and provides
decision trees to select most optimum formulation development strategy. While some formulation technologies
such as multi-layer tablets, multiparticulate systems, active film coating, and hot-melt granulation are discussed in
more detail, a few specialized technologies are also introduced briefly to the readers.
Keywords:  Fixed dose combination, FDC, formulations, an active coating, HME, bi-layer tablet

Overview of fixed dose combination
products of oral dosage forms
Fixed dose combination (FDC) drug products are very
common for almost all therapeutic areas. Many different
types of oral, parenteral, and inhalation FDC formulations
are commercially available.[1] Reviews of the Physicians’
Desk Reference (PDR) and United States Pharmacopeia
(USP) in 2005 revealed that there were 150 FDC products,
mainly cardiovascular and cough medicines, listed in
PDR and 80 in USP.[2] The difference in numbers for both
compendia was attributed to the lag time for a marketed
product to be a USP product. Nevertheless, both numbers
showed continued growth of the FDC products. Similarly, it
was shown that the top five therapeutic areas for approved
FDCs are infectious, cardiovascular, hormone, allergies
and pain by surveying the oral FDC products listed in the
2010 PDR.[3] Majority of the FDCs are composed of two
drug components, only 18 have three drug components,
and only one human immunodeficiency virus (HIV)
FDC has four drug components.[4] Among cardiovascular
agents, nearly 80% of the FDCs are for hypertension[5];
FDCs for HIV/AIDS ranked top in infection; most of FDCs
in metabolic diseases are for diabetes.[6] Among the routes
of administration for the FDC products, oral delivery
ranked much higher than any others, followed by inhala-
tion. This review article is mainly focused on the FDC oral
solid dosage formulation and process development.
According to the Drugs@FDA website, 26 out of the
101 Food and Drug Administration (FDA)-approved New
Drug Applications (NDAs) are FDC products in 2010. A
list of the FDC products at different development stages
in 2009 and 2010 have been tabulated in Table 1 in order
to assess the current trends in the FDC product develop-
ment. Even though the list is incomplete, it is clear that

Address for Correspondence: Dr. Divyakant Desai, Ph.D., Drug Product Science and Technology, Bristol-Myers Squibb Co., PO Box 191,
New Brunswick, NJ 08903-0191, USA. Tel: (732)-227–6458. Email: divyakant.desai@bms.com
(Received 09 September 2011; revised 20 January 2012; accepted 20 January 2012)

1265
1266  D. Desai et al.

Table 1.  Partial list of FDCs at different development stages reported in 2009 and 2010.
Company Indication Combination drugs Status
Takeda Hypertension Candesartan and amlodipine besylate NDA submission in Japan
Takeda Hypertension Candesartan and hydrochlorothiazide Approved by EMEA
Takeda Type 2 diabetes Competact® (pioglitazone HCl and Application withdrawn
metformin HCl) from EMEA.
Bristol-Myers Squibb Type 2 diabetes Kombiglyze XR (saxagliptin and metformin Approved by FDA
Company and AstraZeneca HCl XR)
Kombiglyze (saxagliptin and metformin) Approved by EMEA
Takeda Type 2 diabetes Pioglitazone and sulfonylurea NDA submission in Japan
Novo Nordisk and Sciele Type 2 diabetes Repaglinide and metformin HCl Approved by FDA
Pharma
QRxPharma Pain Morphine and oxycodone Phase III
Abbott Cholesterol Simcor (niacin and simvastatin) Approved by FDA
Schering-Plough Asthma Mometasone furoate and formoterol Validated by EMEA
fumarate
Pfizer and Sigma-Tau Malaria Eurartesim® (dihydroartemisinin + Marketing in Africa
piperaquine)
AstraZeneca and Pozen Relief of signs and symptoms of Vimovo™ (naproxen and esomeprazole Approved by FDA
osteoarthritis, rheumatoid magnesium)
arthritis and ankylosing
spondylitis, and to decrease the
risk of developing gastric ulcers
in patients at risk of developing
NSAID-associated gastric ulcers
Gilead HIV Truvada® and TMC278 Formulation BE achieved
GlaxoSmithKline Benign prostatic hyperplasia Approved by Swissmedic
Duodart® (dutasteride and tamsulosin)
and EMEA
BE, bioequivalence; BPH, benign prostatic hyperplasia; EMEA, European Medicines Agency; FDA, US Food and Drug Administration;
HIV, human immunodeficiency virus; JP, NDA, New drug application.

treatment for both hypertension and type 2 diabetes has
attracted a lot of attention in FDC product development.
Current pipeline in the pharmaceutical industry is rela-
tively empty after a burst of several innovative new com-
pounds; FDCs are the only new therapies that will achieve
very significant growth in sales. Overall, FDCs have been
developed in many different therapeutic areas, and will
continue to be a valuable option in drug development.
Advantages and disadvantages of FDC products
FDC products containing two or more active pharma-
ceutical ingredients (APIs) in a single oral dosage form
are playing important roles in treating various kinds of
diseases, such as cardiovascular, HIV/AIDS, malaria,
and tuberculosis, where polypharmacy is a norm (1). The
FDC products, however, have both non-therapeutic and
therapeutic advantages and disadvantages.
Therapeutic advantages of FDC products
The FDC products provide the opportunities to combine
more than one medicine with different pharmacological
mechanisms into a single dosing unit. This has added
significant clinical values in some therapeutic areas
such as anti-hypertensive, anti-viral, anti-glycemic, and
anti-cholesterol treatment. The clinical benefits of FDC
include but not limited to:
1. Synergistic therapeutic effects of two molecules. This
was noted for Aggrenox®, a combination two oral
antiplatelet agents, dipyridamole and aspirin, which
showed better efficacy than the co-administration of
these drugs.[7]
2. The FDC of amoxicillin and potassium clavulanate
enhances the effectiveness of amoxicillin, because
potassium clavulanate is an inhibitor of β lacta-
mases, protecting amoxicillin from degradation by
β lactamases produced by many microbial organ-
isms.[8] This combination effectively extends the anti-
bacterial spectrum of amoxicillin.
3. Sometimes, the drugs are combined to minimize
the potential drug abuse, such as Suboxone®
(buprenorphine and naloxone) and Lomotil®
(diphenoxylate and atropine). Buprenorphine and
naloxone are combined in Suboxone® to prevent the
possibility of injecting the product by opioid addicts
to get high on buprenorphine, a partial opioid ago-
nist. Naloxone, an opioid antagonist, will generate
withdrawal symptoms if Suboxone® is injected.[9]
Similarly, diphenoxylate/atropine combination is
used to counter opioid-like effect of diphenoxylate
at high doses with anticholinergic effects of atro-
pine.[10]
4. The combination of short-acting pseudoephed-
rine and long-acting loratidine for the coverage
of extended period in allergy products such as
Claritin-D®.
5. Minimizing the drug-resistant microorganisms,
especially for anti-viral and anti-tubercular drugs.

 Pharmaceutical Development and Technology

 Formulation design and development of fixed dose combinations  1267
For the HIV treatment, efavirenz, emtricitabine, and
tenofovir are combined in Atripla®, a single tablet.
For the treatment of tuberculosis, FDC products
containing rifampicin, isoniazid, pyrazinamide, and
ethambutol are available.[11]
6. Sometimes, one drug is combined with another
drug to improve safety/tolerability. For example,
in Arthrotec® tablet, misoprostol, a prostaglandin
analog, is combined with diclofenac, a non-steroidal
anti-inflammatory drug (NSAID).[2] Misoprostol
has gastro-protective property which reduces gas-
trointestinal (GI) irritation/ulceration caused by
diclofenac.
7. The FDC products improve patient compliance
by reducing dosing unit burden. For example, the
well-known cocktail therapies in HIV/AIDS patients
involve the combination of several active ingredients
to create multiple obstacles to HIV replication and
to reduce the possibility of drug resistance.[12] The
patient compliance is very important to avoid devel-
opment of the drug resistance.
Non-therapeutic advantages of the FDC products
1. The evolving FDC for anti-retroviral products signifi-
cantly improves HIV patient’s compliance, especially
for those in the third world countries, not only due to
the reduced dosing burden, but also due to the fact
that the FDC products tend to be cheaper than mul-
tiple individual products.
2. The FDC products reduce manufacturing cost com-
pared with the costs of manufacturing separate prod-
ucts. At the same time, the FDC products simplify the
logistics of distribution.
3. Finally, the FDC products offer an opportunity for the
pharmaceutical companies to sustain their product
pipeline as the industry faces a slowdown in block-
busters drugs.[13] This was evidenced by the fact that a
significant amount of newly approved drug products
are FDCs.
Disadvantages of the FDC products
In spite of above-mentioned advantages, there are some
disadvantages of FDC products.
1. FDC products reduce dosing flexibility. To compen-
sate the reduced dosing flexibility, multiple strength
combinations are developed to cover common
doses for each drug component of the FDC product.
However, some disease treatments or some patients
require frequent dose adjustments where the FDC
products are not very useful.
2. It is more difficult to pin point the cause of the adverse
drug reactions of the FDC products as more than one
drug is administered in a single dosing unit.
3. FDC products could be challenging for pharmacists
to monitor patients’ drug therapy. For example,
metformin is contraindicated for men and women
© 2013 Informa Healthcare USA, Inc.
when the serum creatinine is 1.5 mg/dL and 1.4 mg/
dL, respectively.[14] This stipulation may be easily
missed for FDC products containing metformin.
4. Pharmacists and physicians can easily overlook the
limit of certain drugs in FDCs. An example is acet-
aminophen for which the maximum daily dose is 4 g/
day.[14] Many patients, in addition to acetaminophen,
can be on more than one FDCs of acetaminophen
with codeine, oxycodone, or hydrocodone for pain
management, the limit can be missed.
5. Since the FDC contains multiple drugs in one tablet,
sometimes, the tablet size may be too big to swal-
low for pediatric and elderly patients. For example,
for type 2 diabetes, metformin is the main pillar of
the therapy with the dose range of 500 mg–2000 mg.
When any other antidiabetic agents are combined
with metformin, the tablet size can be too big to swal-
low easily.
Regulatory considerations and guidance on
FDC products
The regulatory authorities have recognized the impor-
tance of FDC drug products on public health by devel-
oping relevant guidelines. In the United States, the basic
requirements for the FDC prescription drugs for humans
have been defined in the code of federal registration 21
CFR 300.50. A FDC is defined as “Two or more drugs may
be combined in a single dosage form when each compo-
nent makes a contribution to the claimed effects and the
dosage of each component (amount, frequency, dura-
tion) is such that the combination is safe and effective for
a significant patient population requiring such concur-
rent therapy as defined in the labeling for the drug.”
There was a draft guidance for the pharmaceutical
industry regarding the clinical evaluation of estrogen/
progestin combination drug products published in
2003.[15] The first FDC related guidance for the pharma-
ceutical industry was implemented for anti-retroviral
products by FDA in 2006.[16] This guidance was “intended
to encourage sponsors to submit applications to the FDA
for approval of the FDC products and co-packaged ver-
sions of previously approved anti-retroviral therapies
for the treatment of HIV”. After reviewing the guidance,
readers would understand “To which products does this
guidance apply?”, “What regulatory procedures apply to
FDC and co-packaged HIV products?” and “What are
the characteristics of the potential regiments for FDC or
co-packaged HIV therapies?” Considerations for clinical,
clinical pharmacology and biopharmaceutics, chemistry,
manufacturing, and controls, microbiology/virology and
labeling were provided in this document. Other regulatory
considerations, such as exclusivity, user fees, pediatric
studies and post-approval issues were addressed as well.
There are two possible NDA pathways for FDC prod-
ucts for drugs already approved by the FDA. They depend
on the source of the data. For 505 (b) (1), a sponsor gen-
erated all necessary data or has a permission to use the
data. For 505 (b) (2), a sponsor did not generate necessary
1268  D. Desai et al.
data or has right to reference the data, but would rely on
relevant published data or literature. The details are pro-
vided in the FDA guidance.[17] The main advantage of 505
(b) (1) is the longer product exclusivity compared to the
limited exclusivity of 505 (b) (2).
Until recently, FDC products were only approved for
drugs previously approved as single entity. However, it
has been shown that certain diseases such as hepatitis C,
viral resistance to single molecule can develop quickly.
Therefore, it is more beneficial to co-develop molecules
starting very early in the development. With advances in
genomics and cell biology, regulation has also advanced
in concert.[18] Most recently, in December 2010, a new
FDA draft guidance regarding the co-development of
two or more unmarketed investigational drugs for use in
combination was published in the Federal Register and
is soliciting public comments.[19] This guidance has pro-
vided recommendations to the industry in “determin-
ing whether or not, a co-development is an appropriate
development option.” This document has also listed a
number of regulatory procedures to be considered in co-
development of drugs for FDC products.
For the regulatory landscape outside of the United
States, the interested readers can refer to the World Health
Organization’s Guidelines for Registration of Fixed Dose
Combination Medicinal Products for general advices.[11]
In March 2009, the World Health Organization approved
the expedited process to review FDC medicines and co-
packaging of existing therapies for the treatment of HIV/
AIDS in developing countries.[20]
Formulation development strategies for
FDC oral solid dosage forms
In general, drugs are selected for FDC development
based on fundamental understanding of their pharma-
cological mechanisms, drug–drug interactions, clinical
experience, and pharmacokinetic profiles and manufac-
turability. Synergistic therapeutic effects are desired, but
very difficult to demonstrate.
Establishing bioequivalence (BE) of drugs in FDC to
drugs co-administered as individual entities is a very
common approach compared to therapeutic equivalence
(TE) as a clinical strategy for FDC development. The main
reason is that the BE studies are shorter and less resource
intensive compared to the TE studies. From a clinical
perspective, drug–drug interactions in the FDCs need to
be evaluated carefully. The possible food effects on the
drug components in the FDC may be different as well.
Dose proportionality consideration for bio-waiver
FDCs often require multiple dose strength combinations
based on the mono therapy regime. The multitude of
dose strength combinations will not only impact formu-
lation design, but also increase BE complexity. If dose
proportion is feasible, it is possible to obtain bio-waivers
for the lower strength combinations after establishing the
BE for the highest strength combination of the FDC. Dose
proportion may also make the formulation design and
 Pharmaceutical Development and Technology
process development easier. In addition, discussion with
regulatory authorities may be critical in clinical design or
even determining the feasibility of a drug combination.
Extension of patent life
One common strategy to protect a drug with pending
patent expiration is to develop its FDC with another new
drug that has longer patent protection. For example,
valsartan (Diovan®), a blockbuster anti-hypertensive
drug with annual sales of more than $8 billion, will lose
compound patent protection in the United States in
2012. Aliskiren (Valturna®) is the 2007 FDA-approved
new anti-hypertensive drug. The FDC tablet contain-
ing valsartan and aliskiren will not only provide clinical
benefits, but may also help to retain some of the Diovan®
market share after its patent expiration. The usefulness
of FDC to preserve market share of the individual best-
selling drugs has mixed produced mixed results so far.
For example, Caduet®, a combination of two multibil-
lion dollar drugs, Norvasc® (amlodipine) and Lipitor®
(atorvastatin), only managed to have a few million dol-
lars in annual sale.
Formulation development challenges and strategies for
FDC oral solid dosage forms
Formulation design and process development for FDC
products are typically more challenging than corre-
sponding single entity products.[21] Many factors can
contribute to the complexity in formulation design and
process development. If combined drug strengths are too
high (>1000–1500 mg), the tablet size of the FDC product
can become critical in achieving patient acceptance.
Disproportionate drug dose combinations can be
very challenging in achieving good content uniformity,
especially in weight control of low dose layer of multi-
layer tablets that contains low dose in the second layer.
For example, drugs like metformin where dose as high
as 1000 mg in one layer is combined with sulfonylureas
with the low dose of 2.5 mg in the second layer. Chemical
compatibility among all drugs as well as excipients in
FDCs are always the first step in formulation design and
process development. Efforts should be made to stay with
the same dosage form as that of the single entities. For
example, if the single entity is a tablet, then select tablet
as the dosage form in monolithic or bi-layer tablet. A bi-
layer tablet is needed if there is incompatibility between
the drugs or different drug release profiles are needed.
For some reasons, if a tablet dosage form is not feasible
then multiparticulate dosage form should be pursued
(Figure 1).
Clinical challenges
Instead of waiting for the FDC formulation develop-
ment to be completed, clinical studies may be initiated
by co-administering two individual single entity tablets.
Once the FDC product is developed, then a BE study can
be conducted to demonstrate that the co-administered
components are bioequivalent to those from a FDC
 Formulation design and development of fixed dose combinations  1269
Figure 1.  Decision tree of the formulation design of FDC.
product. This strategy removes the FDC product develop-
ment from the rate-limiting path in the overall develop-
ment program. However, if the potential risk for BE failure
is high then this strategy is not advisable. The BE failure
risk assessment needs to be conducted using the frame
work of biopharmaceutical classification system (BCS)
and clinical experience with two drugs identified for
FDC. The BE failure risk is higher for BCS Class 4 drugs,
the drugs with low solubility and low permeability, com-
pared to other BCS classes. The potential BE failure risk
also needs to be taken into consideration in selecting the
fixed dose formulation approach. Ideally, the dissolution
profiles of the components from a FDC should be similar
to those of respective single entity tablets.
Another challenge is how to dose FDC product with
regard to meal. For example, metformin is dosed after the
meal for better GI tolerance. In contrast, sulfonylureas
are dosed prior to meal to avoid possible hypoglycemia.
Interestingly, the metformin combination products are
given with meals. In addition, some drugs are known
to have positive or negative food effects. In case of posi-
tive food effects, the drug bioavailability is increased
significantly when given with a high fat meal compared
to when administered in a fasted state. For the negative
food effect, the bioavailability is decreased significantly
when given with high fat meals. FDCs of such drugs
could be very challenging. The only known formulation
approach to overcome positive food effect is a softgel for-
mulation containing long chain and/or medium chain
fatty acids. The major limitation of this approach for FDC
© 2013 Informa Healthcare USA, Inc.
is finite volume. Therefore, for this approach to succeed
the doses have to be small or drugs should have high lipid
solubility.
Formulation design and process development for FDC
oral products
Various formulations and manufacturing processes have
been successfully used in commercial FDC products.
Several commonly used approaches are reviewed briefly
in light of their inherent advantages and challenges. An
example decision tree on how to select the manufactur-
ing process for a FDC product is shown in Figure 2.
Monolithic systems
When two or more drugs are chemically compatible
with each other, a monolithic system in tablet solid dos-
age form may be considered first during formulation
development. Figure 1 briefly describes an example
decision tree in determining whether a FDC product can
be developed into a monolithic system in a much sim-
plified scenario. A monolithic FDC product is similar to
single entity formulation except it contains at least two
active ingredients. However, whether or not being able to
achieve BE using monolithic for all drugs in FDCs have
to be carefully evaluated. For example, when combining
one BCS II drug and one BCS III drug in one FDC, due
to different dissolution profiles and absorption mecha-
nisms, even though they may be chemically compatible,
monolithic system may not be a suitable choice. For
example, a formulation matrix used for a BCS Class III
1270  D. Desai et al.
Figure 2. Decision tree for manufacturing process selection
for FDC.
drug may impair wetting and dispersion of a BCS Class
II drug, it may make its bioavailability highly variable. In
such cases, a monolithic system is not desired.
Multi-layer tablets
As an extension of the well-known conventional single-
layer tablets, multi-layer tablets provide a simplified
treatment regimens, greater patient convenience and
compliance.
Chemical stability of layers  From drug product develop-
ment perspective, bi-layer tablets, sometimes tri-layer
tablets, are a convenient way to formulate incompat-
ible drugs in a single tablet. It is the approach that
often results in significantly improved overall chemical
stability of the drug product. In addition, it is a conve-
nient approach to enable the inclusion of an immedi-
ate release loading dose and another controlled release
dose for sustained action in a multi-layer tablet in
which the API included in all layers could be the same
or different from each other.[22–24] However, in some
cases, multi-layer tablets are not specifically developed
for FDC products when there is only one API included
as the middle layer sandwiched with two swellable
and floatable composite matrix layers to provide a
zero-order drug delivery or bimodal drug release pro-
files in the fast/slow/fast mode.[25,26]
Chemical instability and buffer layer  If the chemical
stability of the APIs in a bi-layer tablet system is still not
acceptable due to the interaction at the layer interface,
an alternative is to add a third buffer layer between the
two API-containing layers in order to further reduce
the chemical reactions. For example, an alkaline layer
 Pharmaceutical Development and Technology
containing calcium carbonate, magnesium oxide, mag-
nesium carbonate, or sodium phosphate monobasic
was evaluated as the buffer layer to prevent the chemi-
cal reactions between pravastatin and aspirin in two
separate layers in a FDC tri-layer tablet.[27] Additionally,
the drug–drug interaction from the two separate layers
with an interface may manifest in such a way that the
in vitro dissolution release profile of one API is affected
due to the change of the microenvironment caused
by the other API or excipients in the second layer. It is
always valuable to evaluate whether or not one drug
will impact another drug’s in-vitro dissolution profile
with or without pH changes.
Once the chemical stability profiles of all drugs in a
FDC are satisfactory, multi-layer tablets present some
unique challenges in terms of obtaining acceptable
tablet physical characteristics compared to the conven-
tional monolithic tablets. The challenges may include
insufficient overall tablet tensile strength which may
lead to excessive friability, delamination at the interface
between layers, or capping within individual layers. In
addition, unsatisfactory weight control for individual
layers or overall tablet may lead to problematic content
uniformity of the APIs.
Layer formulation composition similarity  In order to miti-
gate the challenges and to avoid the pitfalls of multi-layer
tablet formulation development, a preferred approach
is to maintain certain level of formulation similarity
between layers. This view point is further elaborated using
bi-layer tablets as an example. If sufficient similarities
can be maintained between the two layers, there would
be less potential for the aforementioned bi-layer tablet
process issues to occur. Depending on the difference
of the drug dose that has to be included in each layer, it
would be beneficial to formulate both layers with similar
composition and weight. When the drug loading is high
in only one layer for clinical reasons (e.g. 300–600 mg),
or when the weight of one layer has to be kept high for
formulation reasons (e.g. 800–1200 mg), it is necessary to
keep the overall tablet weight low enough (e.g. 1000–1500
mg) for good patient compliance. In such cases, when
the weights of both layers have to be significantly differ-
ent, one should try to make compositions of both layers
to share some common excipients. Additionally, it is a
good practice to keep the weight ratio of the two layers
not more than 1:6. The similarities of the weight and/or
composition of the two layers subsequently lead to simi-
larities of the physical properties of the granular/powder
materials for tablet compression such as particle size and
distribution, density, and flow. Consequently, it would
be more achievable to obtain the similarities of the tab-
let compaction profiles of the two layers, which benefits
the physical integrity of a bi-layer tablet. It has also been
discovered that different levels of layer swelling capac-
ity in a bi-layer tablet may lead to layer separation at the
interface, especially when exposed to a higher relative
humidity environment (e.g. relative humidity of 75% and
 Formulation design and development of fixed dose combinations  1271
higher). The reason may be the increased level of shear
stress at the layer interface caused by the different extent
of swelling of individual layers (unpublished data).
Process parameter and physical integrity  When different
formulations have to be used for each layer in a multi-
layer tablet, it is often imperative to adjust the tablet
compression process in order to achieve satisfactory
tablet physical quality attributes. Sufficient adhesion at
the interface of the two layers is necessary to maintain
the physical integrity of a bi-layer tablet. Insufficient
adhesion could lead to delamination which is defined
as the distinct layer separation along the interface. It was
found that the compression force for the first layer was
a critical factor affecting the propensity of bi-layer tablet
delamination (unpublished data). The function of the
first layer compression force, often in the range of 2–18
kN, is to tamp the material in order to moderately reduce
the volume and smooth the surface of the first layer, and
make room for deposition of the second layer material.
In general, higher compression force results in higher
tensile strength of the first layer and smoother layer sur-
face before the second layer material is fed into the die.
However, a decrease of the surface roughness of the first
layer sometimes results in an increase of the delamina-
tion potential mainly by reducing the mechanical inter-
locking of the interparticulate adhesion between the two
layers. Such phenomena have been generally observed
regardless whether both layers have the same or different
formulation compositions, or whether each formulation
consists of single ingredient (e.g. microcrystalline cellu-
lose) or multiple ingredients (e.g. microcrystalline cellu-
lose and lactose monohydrate) (unpublished data).
The delamination and capping could occur within one
of the layers (intralayer), or between layers (interlayer).
The primary reasons for capping could be insufficient
cohesive/adhesive interaction among granules/ingredi-
ents, low level of moisture content, air entrapment dur-
ing compression, or excessive compression force applied
during compression. The delamination tendencies of
bi-layer tablets have been reported by Podczeck[28] and
especially the interfacial relaxation during tablet ejection
has been covered nicely by Anuar et al.[29] Another aspect
of the bi-layer tablet compression is about the sequence
of layer compression for the same purpose of reducing
the potential of interlayer delamination or intralayer
capping. A general rule of thumb for determining the
sequence of bi-layer tablets compression is to compress
the materials with higher fragmentation tendency as
the first layer, and the materials with more deformable
capacity as the second layer. The compaction character-
istics of individual layers can be obtained by evaluating
the granule/powder compactibility profiles such as the
compact tensile strength versus solid fraction curve.[30]
Thirdly, it is an effective method to use one-way or two-
way tapered die to reduce the level of air entrapment
during bi-layer tablet compression. On the same token,
the use of pre-compression force for individual layers or
© 2013 Informa Healthcare USA, Inc.
adjusting the compression zone in the die, especially for
the second layer, to a shallower position (closer to the
upper surface of the die) can reduce the occurrence of
the delamination/capping. Lastly, the layer of smaller
drug dose or press weight is considered to be compressed
first for the purpose of obtaining satisfactory API content
uniformity.
It is advisable to optimize the first layer compression
force in order to minimize the delamination potential.
Subsequently, the second layer weight variation caused by
the volume variation of the first layer can be reduced. On
the other hand, the sequence of layer compression is also
evaluated in combination with the compaction properties
of individual layers. Fortunately, the technology advance-
ment in tablet press has offered great assurance in bi-layer
tablet compression which is one of the most important
unit operations for this dosage form. Bi-layer tablet presses
have been routinely used to manufacture commercial scale
bi-layer tablets since 1990’s.[31] Many bi-layer tablet presses,
such as Piccola, Oystar Manesty, Fette, Killian, Korsh, and
Curtory, are available to serve both product development
and commercial production purpose. These tablet presses
are often featured with critical functions including pre-
compression/tamping station for each layer, automatic
first layer sampling, or automatic layer weight control for
all layers during multi-layer tablet compression.
Friability and tensile strength testing  As the physical
integrity is a primary concern for multi-layer tablets, the
conventional tablet friability test using a friability tester is
still widely used. There has been some progress in char-
acterizing multi-layer tablets. X-ray tomography was used
as a non-destructive testing to visualize the delamina-
tion, cracks, voids, and other fracture patterns inside the
tablets and explore the mechanical failure mechanisms
of multi-layer tablets by acquiring three-dimensional
images for bi-layer tablets (unpublished data). The com-
paction behavior of binary mixtures and bi-layer tablets
of microcrystalline cellulose and lactose was investigated
with this method.[32] It was shown that for binary and bi-
layer tablets with the identical compositions consisting
of microcrystalline cellulose and lactose, the apparent
tensile strength of the compact was generally comparable
for the powder systems studied and the fracture patterns
depended upon the ingredient weight ratios and process
conditions including the sequence of the layer compres-
sion. Another method, non-contact laser profilometry,
was used to characterize the topographic profiles and
quantitative roughness of various surfaces of the bi-
layer tablets.[33,34] The results suggested that the localized
stored energy released by volume expansion in the radial
direction maybe responsible for the fracture of tablets
along the interface for a bi-layer tablet. Additionally,
the air-coupled acoustic technique, a non-contact/non-
destructive method, was used to determine the mechani-
cal properties of the bi-layer tablets.[35] The mechanical
properties, such as Young’s modulus, Poisson’s ratio, and
mass density, were determined based on the resonance
1272  D. Desai et al.
frequency measurements and computational calcula-
tions. It is not only that this technique had the capability
of detecting the weak bonding at the interface, but also
it had the potential to monitor a bi-layer tablet com-
pression process online. More in-depth understanding,
characterization, and modeling of the bi-layer tablets,
especially the establishment of a priori method in mate-
rial selection and fracture mechanics prediction in for-
mulation and process development are of great interest
to many researchers.
Multiparticulate systems
In theory, a multiparticulate system could be a good
choice suitable for the development and manufacture
of FDC products. The ways of combining multiple APIs
to obtain various release profiles in one dosage form
presents fewer limitations from a pharmaceutical devel-
opment perspective. The most used multiparticulate
system for oral solid dosage form contains pellets and/
or powders compressed into tablets or encapsulated
into capsules. One or several APIs may be introduced
into a pulsatile drug delivery system or alike during the
manufacturing process. The main technology of making
such systems is extrusion/spheronization to form pellets
followed by one layer or multiple layers of film coating.
Based on the physicochemical properties of the APIs and
excipients, many variations in this technology have been
used. The preparation of pellets or spherical granules by
extrusion/spheronization is a more established method
with the advantages of narrower particle size distribution
of the pellets with lower friability suitable for film coating
from product manufacture stand point.[36] The extrusion/
spheronization process includes four steps: granulation
to prepare the wet mass, extrusion to shape the wet mass
into cylinder-shaped extrudates, spheronization to break
the extrudates and round off the particles into spheres,
and drying of the pellets. The equipment requirements
and manufacturing process critical points for the extru-
sion/spheronization process, as well as for other meth-
ods of making pellets, are well summarized by various
researchers.[36–40] Another important aspect of making
multiparticulate systems is how to incorporate APIs into
the pellets. In most cases, the APIs may be mixed with the
ingredients during the process of making pellets.[41]
Pelletization by drug layering  Another way could be lay-
ering the drug solution or suspension onto sugar pellets,
followed by coating of a swelling layer and a controlled
release layer.[42,43] Some ready-to-use pellets made with
sugar (e.g. Suglets®), microcrystalline cellulose (e.g.
Ethispheres®), or starch (e.g. Corn Starch Spheres®) are
also commercially available. Drug can also be incorpo-
rated into the highly porous pellets (33.2% porosity) by
soaking the pellets into a drug solution or a drug-contain-
ing supercritical fluid.[44] As a variation of the pellets with
or without the controlled release film coat, mini-tablets
having immediate or controlled release profiles can be
used in the multiparticulate systems.[45,46] The pellet can
 Pharmaceutical Development and Technology
also be combined to bring together an immediate release
and extended release dosage form together. For example,
extended release beads of propranolol can be combined
with an immediate release hydrochlorothiazide table in
a capsule.[2]
In practice, many concepts of the development and
manufacture of the multiparticulate dosage forms con-
taining one drug may be borrowed for FDC products. The
common scheme of using multiparticulate system for
FDC products is to combine the immediate release and
controlled release components in one dosage form.[47]
However, the applications have not been much used for
the FDCs, especially for marketed FDC drug products.
The main contributing factors may lie in the fact that the
technical complexities of the product development and
the requirements of more unique pellet manufacturing
equipment and process. Although the pelletization for
the manufacture of multiparticulate drug delivery sys-
tems, such as extrusion-spheronization, is considered
well established, they are far from simple. Small changes
in the formulation and process may cause significant
effects on the quality attributes of final products.[48–50]
Other technologies with less demanding requirements,
such as multi-layer tablets, have provided good alterna-
tives for the multiparticulate dosage forms for FDC drug
products.
Hot-melt extrusion approach
HME has been well established in the plastic and food
industries since 1930’s. It has gained increasing atten-
tion in the last 10 years in the pharmaceutical industry.
Traditionally and currently, hot-melt extrusion (HME)
technology was mainly used to make amorphous drugs
in drug development. HME technology has been used
in pharmaceutical industry to make not only sustained
release formulations, but also immediate release for-
mulations. A new hot-melt granulation approach to
densify the granulation and improve compressibility
using HME technology has been reported as well.[51]
It is well suited for the immediate release FDC prod-
ucts containing one or two drugs of higher dose (e.g.
300–1000 mg). The drug may exist in either crystalline
state or amorphous state depending on the process
conditions.
The main working principle of the melt granulation is
to reduce polymer viscosities at higher temperature and
increasing its surface area resulting in improved com-
pression characteristics of the granules containing drug
and polymer. The processing temperatures are typically
set between the glass transition temperature (Tg) of the
polymer and melting temperature of the drug substance.
As a result, the drug substance remains in crystalline state
in most cases. Several polymers like hydroxypropyl cel-
lulose, hydroxypropylmethylcellulose, and Poloxamer®
are commonly used in the melt granulation technology.
Other excipients, especially plasticizers, can impact the
required process temperature significantly. The process
conditions, such as torque force and feeding speed, may
 Formulation design and development of fixed dose combinations  1273
make actual process temperatures much higher than
the set temperature. Compared to other conventional
granulation technologies, the melt granulation is par-
ticularly suitable for the formulations with higher drug
loading requirements. This could be particularly benefi-
cial for some bi-layer FDC products if both drug doses
are high. In some cases, the drug loading was increased
from 50% w/w to 80–90% w/w by using the melt granu-
lation technology. For example, if both drug doses are
300 mg in a bi-layer FDC product, the total tablet weight
was reduced from 1200 mg (50% w/w drug loading) to
750–667 mg (80–90% w/w drug loading), which is more
patient friendly (unpublished data).
It was also reported that the melt granulation dem-
onstrated enhanced chemical and physical stabilities for
moisture sensitive compounds.[52] The output of Leistritz
50 mm extruder can reach 50–80 kg/h, and Leistritz
100 mm extruder can be even higher. Compared with
wet granulation, melt granulation has shown improved
processability and quality control. However, the melt
granulation has its own disadvantages, such as the chal-
lenges with thermo labile compounds, physical stability
of extrudates. Another frequently faced challenge is the
black specks in granules and tablets, which may be due
to the prolonged excipient residence time in an extruder
during the processing, causing some charring. This can
be overcome through optimizing the formulation and
process conditions. In addition, cleaning of the extruder
is much more time consuming than for other granulation
equipment.
The melt granulation technology has been success-
fully used in developing multiple commercial FDC prod-
ucts by various pharmaceutical companies. As a new
granulation approach, there is no clear decision process
regarding the selection of polymers, plasticizers, and
other excipients. More in-depth investigation and under-
standing of this technology is needed.
Active film-coating approach
An active film-coating technology is often used to prepare a
FDC tablet formulations. For example in Claritin-D™, lorata-
dine and pseudoephedrine sulfate are coated on extended
release pseudoephedrine cores.[53] Upon oral administra-
tion, the coating dissolves immediately to release loratadine
and pseudoephedrine to provide initial dose followed by
extended release of pseudoephedrine from the tablet core
matrix.[53] Similar approach was also adopted for Advicor™
where lovastatin was coated on extended release niacin
tablets.[54] One important advantage of the active coat-
ing technology is that the release profiles of two different
drugs are maintained.[55] There are FDC tablet formulations
where the main objective is to keep two actives apart to
minimize chemical interactions. In such cases, either one
active could be included in the core tablets followed by the
active coating of another active. Alternatively, both actives
can be coated on the inert cores by applying two separate
coating layers separated by an inert coating layer, if needed
as illustrated in Figure 3.[56]
© 2013 Informa Healthcare USA, Inc.
Figure 3. Active film coating for fixed dose combination
tablets.
Compression sensitive molecules  Degradation of some
molecules is augmented by commonly used pharma-
ceutical operations such as dry or wet granulation,
milling, or tablet compression. A FDC tablet formula-
tion involving such a molecule is even more challeng-
ing. One possible solution is to formulate a traditional
tablet formulation for a molecule which is not sensitive
to common pharmaceutical operations as the core
tablets followed by depositing the sensitive molecule
on the core tablets by active coating. By using such
approach, common pharmaceutical operations for a
sensitive molecule can be avoided.[56]
Stabilization of acid and base labile molecules Some
molecules are prone to acid as well as base catalyzed
degradation. This challenge is further aggravated
when such a molecule needs to be formulated in a
FDC. One proposed solution is to make tablet core
of the relatively stable molecule and to use an active
coating approach for the acid or base labile molecule.
One inherent advantage of the active coating is that
it provides relatively higher drug to excipient ratio
compared to having such molecule in the tablet core.
For example, 1 mg of the acid and base labile mol-
ecule in 100 mg core tablet will have drug to excipient
ratio of 1/100 compared to having such molecule in
10 mg coating material. The later will have drug to
excipient ratio of 1/10. With higher drug to excipient
ratio, the number of excipient sites available to react
with the drug molecule is reduced providing better
stability.[57]
Challenges for active film coating  For traditional tab-
let formulations developed using direct compression,
wet granulation, or dry granulation technology, API is
weighed and mixed with other excipients as a part of the
manufacturing process. In the active coating approach,
API is sprayed on the tablet cores. There are two main
challenges in this approach. First, how to determine the
coating end point so that when the coating is stopped,
the tablets will have targeted potency. Second, given
the variability inherent in the coating operation, how
to make sure that all the tablets will have satisfactory
content uniformity.
Determining the coating end point  For traditional cos-
metic coating, the coating end point is determined
either based on the amount of suspension sprayed or
1274  D. Desai et al.
the weight gain of the core tablets. This approach has
been further modified for the active coating. During
the active coating, tablet samples are taken periodically
and analysed not only for weight gain but also for the
amount of API deposited by performing an in-process
assay. As shown in Figure 4, after 50% coating, a linear
relationship has been observed between the weight
gained and amount of API deposited.[56] Normally, at
about 75%–80% amount sprayed, the amount of API
deposited is determined. Based on that information,
additional amount of suspension needed to get the tar-
get potency is determined.
Content uniformity  For the traditional tablet formu-
lations, the amount of API needed for the batch is
weighed and mixed with the formulation excipients
followed by dry or wet granulation. The API is locked
in the granulation step with the rest of the excipients.
Since the API is intimately mixed with the excipients,
the proper control on the weight variation of the tablet
ensures satisfactory tablet content uniformity. On the
other hand, in the active coating, the API is sprayed
along with the coating materials on already formed core
tablet. Therefore, the factors governing the content uni-
formity of active coated tablets are very much different
than those of the traditional tablets.[58] Control on the
spraying operation is vital for the satisfactory content
uniformity of the finished products. Essentially, when-
ever tablets come in front of the spray zone, the API
and coating materials get deposited on them. Recent
development in the active coating technology has
made it possible for formulators to use this technology
to develop FDCs.[59–63]
Electrostatic coating
This technology was developed by the Phoqus Company.
Tablet core with some conductive property with one of
the FDC drugs is prepared. Using electro-magnetic field,
the opposite charge is applied to another drug with some
coating material. Since the charge of the core and coating
is opposite, the coating gets deposited on the core tab-
lets electro statically. The coated tablets are heated up to
about 70–100°C for the coating adhesion. This technique
has been shown to be able to deposit 10 mcg–5 mg of the
Figure 4. Middle (active) layer monitoring (2.5 mg API coated
tablets).
 Pharmaceutical Development and Technology
second drug. This technology cannot be used for heat
sensitive molecules. Moreover, the maximum amount
applied can be limited to 5 mg and there are specific
requirements for core and coating materials in terms of
conductivity.
Compression coating technology
In this approach, a single tablet containing an immediate
or controlled release drug core tablet is enveloped by a
compression-coated compartment containing a second
drug with same or different in-vitro dissolution profile.
This technology may be suitable for heat and solvent sen-
sitive drugs.
Co-processing approach
The co-processing approach where two excipients or a
drug and an excipient are crystallized together from a
solvent to either improve compressibility[64] or dissolu-
tion, this approach has been extended for the develop-
ment of FDC. The main challenge in this approach is
to identify solvent and anti-solvent which do not alter
polymorphic form of the drug substances. Mohammed
et  al. used the co-processing approach to combine
nevirapine and stavudine to overcome content unifor-
mity issue. These two co-processed drugs were com-
bined with lamivudine to form a triple combination
tablet.[65]
Enrobing technology
This patented technology from the Banner Technology
enrobes tablets with either a gelatin or material with
non-animal origin.[66] The enrobement process uses coat-
ing die techniques in which the tablets to be enrobed
are introduced individually between two sealable films
positioned between opposing matching dies. With the
flexibility to include the second drug included in the
enrobing film, this technology offers proprietary imme-
diate/modified release technologies for incorporation of
drug in the FDC products.
Liquid dispensing technology
This is a proprietary technology developed by Glaxo
Smith Kline(GSK).[67] In this technology, the tablet can
be an inert core or may contain an API. On one side of
the core surface, there is a small well or recess. In this
well, drug and polymer dissolved in an organic solvent
is deposited using a micro pipette. The organic sol-
vent evaporates leaving behind a thin film of drug and
polymer. On this film, just coating material dissolved
in an organic solvent is deposited. The organic solvent
evaporates leaving behind a thin film coat. Similar
procedures can be repeated on the other side of the
tablet core. Thus, FDC of two drugs can be developed,
if desired, with the inclusion of one or more drugs in
tablet core, a triple combination can be developed. This
technology is very suitable for potent molecules where
drug containment is highly desired since drug is always
deposited in solution.
 Formulation design and development of fixed dose combinations  1275
Conclusion
From a clinical perspective, aging population in many
developed countries will need multiple medications to treat
age related diseases and co-morbidities. FDC products
will continue to be a useful tool to combine medications
with different mode of action to treat disease conditions
with fewer dosing units. As outlined in the article, the
number of FDC products has grown over the years and the
trend is likely to continue. With the increase in growth of
the FDC products, new formulation approaches will also
be invented by pharmaceutical companies. It is hoped that
this review article will give an overview to pharmaceutical
scientists about the challenges and opportunities in the
formulation development of the FDC products.
Declaration of interest
The authors report no conflicts of interest.
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