April 2012 Colorcon® News

In This Issue:


 Understanding Quality by Design (QbD) for Matrix Formulations

Author: Ian Robertson
Global QbD Manager

In response to customer feedback and engagement with regulatory agencies, we have developed an innovative service model for hydrophilic matrix tablets formulated with METHOCEL™ premium cellulose ethers. Colorcon seeks to support not only Pharmaceutical Development (ICH Q8) requirements, but also that of Quality Risk Management (ICH Q9), to ensure drug product quality throughout the product lifecycle.

Colorcon sees QbD as an opportunity to work in partnership with our customers, assisting with efficient drug product formulation development and reducing final product manufacturing risk. Colorcon supports delivery of QbD through knowledge, collaboration and continuous improvement.

In addition to polymer and formulation consultancy, we provide customers with HyperStart® oral solid dose starting formulation service. By sharing our prior knowledge through case studies and experience of developing matrices with METHOCEL™, this builds the fundamentals to mutual success.

Integral to the service model are specific material attribute (MA) samples for METHOCEL™ K chemistry; developed by our Controlled Release Alliance partner, Dow Wolff Cellulosics. Available through Colorcon, the samples support proactive risk assessment of MA to verify robust matrix formulation design and performance. To support and establish control strategy, process trend data for METHOCEL™ is available from Dow Wolff Cellulosics providing assurance of MA control, within manufacturer’s sales specifications.

However, navigation through the regulatory requirements for drug product approval, and especially QbD submissions, can be complex. To support customer approaches, we also supply advisory through our regulatory subject matter experts. Already engaged through a number of QbD initiatives with industry and regulatory agencies, our global regulatory experts can help support opportunities for efficient drug product approval.

Drug product risk also needs managing through its lifecycle, including Security of Supply. Through Business Continuity Planning (BCP) and multiple manufacturing sites, the Colorcon - Dow Wolff Cellulosics Alliance ensures consistent high quality and availability of METHOCEL™ and key excipients globally.

Click here to learn more about Colorcon QbD initiatives.

METHOCEL™ is a trademark of the Dow Chemical Company

 Semipermeable Membrane Coating for Osmotic Pump Technology

Author: Manish Rane, Ph.D.                                                      Formulation Technologies Manager

Push-pull osmotic pump (PPOP) technology is one of the few drug delivery systems that consistently offers true zero order drug release profiles. PPOP consists of a bilayer compressed tablet, with a pull layer, also referred to as drug layer, and a push layer. The core is coated with a semipermeable membrane (SPM) through which a drug delivery orifice is drilled using a laser drill.

Figure 1 represents a cross section of PPOP tablet.


Figure 1

PPOP systems are usually well suited for the delivery of drugs with low aqueous solubility and less than 100 mg dose. Drug release is generally independent of physiological factors such as hydrodynamic conditions, pH, and viscosity of the gastrointestinal content. Moreover, PPOPs exhibit low susceptibility to food effect, and unlike most oral controlled release systems, are generally far less reliant on free water availability in the colon for terminal drug release. The main clinical benefits of these systems are improving patient compliance through more reliable therapeutic effect and better tolerance of the drug treatment. PPOP systems give good in vitro/in vivo correlation (IV/IVC) 1 which is a key advantage during product development and pivotal in securing successful scale-up and post-approval regulatory changes.

The semipermeable membrane (SPM) coating, a critical component of PPOP, controls the rate at which water permeates into the osmotic core; this hydrates the polymer and builds osmotic pressure within the core, eventually leading to a constant release of drug through the orifice. Cellulose acetate (CA) is predominantly used as the semipermeable membrane for this purpose, which is usually applied from an acetone-water mixture. Polyethylene glycol (PEG) acts as a hydrophilic pore-former or permeability enhancing material in the semipermeable film. The way PPOP systems function is by water ingress through the SPM, causing hydration and swelling of the POLYOX™ water soluble polymer in the pull and push layers, as well as generation of osmotic pressure in the core. To sustain the osmotic pressure, and also avoid any deformation or bursting of the SPM, the thickness (and strength) of the film must be carefully optimized.

Figure 2 shows the influence of both weight gain (coating weight thickness) and concentration of PEG on the drug release profiles from PPOP tablets.2 As the coating weight gain (film thickness) increases, drug release becomes slower. As the amount of PEG in the SPM film increases, there is a corresponding increase in the rate of drug release.

Figure 2: Effect of weight gain of SPM and ratio of CA to PEG on time taken for 80% of drug to release (T80%) from PPOP tablets.

Colorcon has conducted a Quality by Design (QbD) process to understand the effect of key formulation parameters such as weight gain of SPM3, concentration of PEG in the SPM4, and molecular weight of PEG2 on drug release profiles. In addition, Colorcon has investigated the processing conditions and effect of preparation of CA dispersion on the film properties and on the drug release profiles.5

Access to this technology, up until now, has been restricted due to the formulation and manufacturing complexity, lack of general know-how as well as the patent landscape. Colorcon has now developed an in-depth understanding of this technology and can provide high quality technical support to customers around the world, reducing time in development, scale-up and process optimization.

The recent webinar titled:
Industry Experts on the Design and Performance of Oral Osmotic Technology, hosted by Colorcon, was extremely popular and proved to be a good forum to share know-how with formulation scientists in this area. Topics covered included formulation design, process selection, scale-up, manufacturing optimization and best practices around different unit operations.

For further information and support for your osmotic pump formulation development please contact Colorcon.

1. Theeuwes F. Oral dosage forms design: status and goals of oral osmotic systems technology. Pharm. Int., 5:293–296, 1984.
2. OSMOTIC PUMP TECHNOLOGIES: BEST PRACTICES, Huatan H., Colorcon Modified Release Forum, London. April 2010.
3. Effect of Semipermeable Coating Composition and Opadry® Top-Coating Systems on Performance of Push-Pull Osmotic Pump Tablets of a Practically Water Insoluble Model Drug Patel P., Liu Q., Missaghi S., Tiwari T., Farrell T., and Rajabi-Siahboomi A., AAPS Annual Meeting and Exposition, Washington DC. June 2011.
4. Development of Push-Pull Osmotic Pump Tablets for a Slightly Water Soluble Drug, Patel P., Missaghi S., Tiwari S., Farrell T. and Rajabi-Siahboomi A., Controlled Release Society Symposium, Washington DC. October 2011.
5. The Influence of Cellulose Acetate Weight Gain and Solvent Ratio on Performance of Push-Pull Osmotic Pump Tablets, Deng H., Martin L., Missaghi S., Farrell T. and Rajabi-Siahboomi A., APV Conference, March 2012.

POLYOX™ is a trademark of The Dow Chemical Company

  Barrier Membrane Coating of Hydrophilic Matrics:
A Strategy to
 Mitigate Potential Food Effect


Authors: Raxit Kumar Mehta - Senior Product Development Scientist and Shahrzad Missaghi - Senior Manager - Product Development                                  

One of the challenges associated with extended release hydrophilic matrices is the potential food effect observed with low soluble drugs, i.e. drug release may be different when taken with food versus an empty stomach. In order to ensure consistent and complete release of insoluble drugs from hydrophilic matrices, they are generally formulated with low viscosity grades of hypromellose (e.g. METHOCEL™, K100 LV premium cellulose ethers). Therefore, drug release is predominantly through erosion of the hydrophilic polymer. The presence of elevated hydrodynamic stress and increased gastric motility, in the fed state, may result in a higher erosion rate of polymer, leading to increased drug release, commonly referred to as “food effect”.

The influence of application of an insoluble barrier membrane (BM) coating over the hydrophilic matrix of a very slightly water soluble drug, hydrochlorothiazide (~ 0.7 mg/mL) was investigated. During dissolution testing, the BM coated hydrophilic matrices of hydrochlorothiazide, showed consistent drug release with very low sensitivity to different hydrodynamic conditions. This approach may offer a potential to minimize food effect. The results of this study were presented at the Annual Meeting of Controlled Release Society, July 2011.

Study Link (PDF 226.58 KB)>>

In another example, a sparingly water soluble drug, acetaminophen (~ 13.8 mg/ml) was used as a model drug. Hydrophilic matrices, containing 50% w/w of drug, METHOCEL™ K100LV Premium and a filler; lactose or a partially pregelatinized starch (Starch 1500®), were developed. Results of dissolution testing from uncoated matrices showed variable drug release at different agitation rates of 50, 100 and 150 RPM. Such in vitro behavior may indicate potentially variable in vivo performance, under fed vs fasted state. The application of a BM coating with Surelease® (aqueous ethylcellulose dispersion), containing an Opadry system as a pore former, resulted in consistent and near zero order drug release from hydrophilic matrices of acetaminophen. Inclusion of Starch 1500, in particular, resulted in less variability in drug release from BM coated matrices when compared to those containing lactose. The ƒ2 value was >50 for Starch 1500 systems; whereas, matrices formulated with lactose resulted in ƒ2 value <50. The results of this study was presented at the Annual Meeting of American Association of Pharmaceutical Scientists (AAPS), 2011.

Study Link (PDF 702.91 KB)>>

The consistency of drug release from BM coated APAP matrices with Starch 1500 were further evaluated using USP Apparatus III (reciprocating cylinder) in bio-relevant media. 

Figure 1 shows that very similar drug release profiles were obtained in bio-relevant media, for simulated fed or fasted conditions, in a USP Apparatus III dissolution machine. Therefore, application of a barrier membrane coating, on the hydrophilic matrix of a sparingly soluble drug, resulted in robust zero order drug release and may offer a possible method to eliminate food effect.

METHOCEL™ is a trademark of the Dow Chemical Company 

 Colorcon and BASF Collaborate on Film Coating Applications Using
 Kollicoat® Smartseal 30 D


Colorcon has developed a pre-formulated additive system for use with Kollicoat® Smartseal 30 D which enables efficient preparation and application of this polymer in taste masking applications. This system further simplifies the preparation of the coating dispersion by lowering the number of materials to be dispensed by 50%, resulting in a reduction of time needed by almost 40%. Hence, customers can reduce their in-house handling effort to a minimum.

Colorcon and BASF announced their collaboration based on BASF’s latest coating innovation, Kollicoat Smartseal 30 D in late 2011.

Next to procuring Kollicoat Smartseal 30 D from BASF, customers now have the option to choose a package from Colorcon including the polymer and a pre-formulated additive system. At Colorcon, we refer to Kollicoat Smartseal 30 D as “the best-in-class reverse enteric polymer for taste masking”, an appraisal representative for the great market appreciation received since its launch late 2010.

Smartseal 30 D is the first water-based dispersion having both taste masking and moisture barrier properties. It was developed to simplify and accelerate aqueous film coating operations. No sticking opens new doors for formulating tablet, pellet, and particle coatings.

To learn more, contact your local Colorcon representative.

KOLLICOAT® and BASF – The Chemical Company are registered trademarks of BASF

 Colorcon Webinars  

    Latest Webinar!  

Making Sense of Excipient Performance for QbD      

This webinar brings together excipient experts from the US Pharmacopeia and the pharmaceutical industry to discuss excipient performance and the impact of QbD on the ability to deliver more robust drug products and mitigate risk.

  • Gain an understanding of the new USP Informational Chapter <1059> on excipient performance
  • Learn best practices for formulating an excipient product using a QbD approach

Presenters: Catherine Sheehan, Director, Excipients, US Pharmacopeia; Ian Roberston, QbD Manager, Colorcon ; Chris Moreton, Vice-President, Pharmaceutical Sciences, Finn Brit Consulting; Dr. Greg Amidon, Research Professor, Pharmaceutical Sciences College of Pharmacy, University of Michigan, and Chair of the USP Excipient Performance Expert Panel

Q&A Panel: Dr. Lawrence Block, Professor of Pharmaceutics, Duquesne University, and Chair, USP Monograph Committee

Click here to register!
Duration: 45 minutes


    On-Demand Featured Webinars  

Inactive Ingredient Database (IID) - Issues with ANDA's

In December of 2011 IPEC met with the FDA’s Office of General Drugs (OGD) to explain their concerns about policy changes to the Inactive Ingredient Database for determining the precedence-of-use levels for some excipients.   These changes were causing a record number of Refuse to File letters being received by manufacturers worldwide. 
  • Find out what guidance IPEC and OGD are working on that will help ANDA sponsors submit the appropriate supporting information in their ANDAs. 
  • Understand what data needs to be submitted to support specific uses of various grades of METHOCEL™ and POLYOX™.
PresenterDavid Schoneker, Director of Global Regulatory Affairs, Colorcon
Click here for access!
Run time: 45 minutes
METHOCEL™ / POLYOX™ are trademarks of the Dow Chemical Company 
Effective Use of Color for Nutritional/Food Supplement Brands
Manufacturers who are interested in learning more about recent trends affecting the use of synthetic colorants in supplements, including their use in film coating will benefit by attending this webinar addressing:
  • The importance of stability testing to achieve reproducible color on your products.
  • New, non-synthetic and non-aluminum lake color options from Colorcon.
  • The benefits of film coating in building brand loyalty.
Presenters: Annabel Bordmann, Market Development Manager; Charles Cunningham, senior Manager, Product Development and Carl Mroz, Director Regulatory Affairs, Colorcon
Click here for access! 
Run time: 45 minutes

If you missed our most recent live webinars, or are interesed in past webinars, visit our On-Demand Webinars page!


 Conversation with…

Subodh Priolkar - Regional Managing Director, Colorcon Inc. South Asia

Vision 2020: India –A Pharmaceutical Superpower

It is an exciting time to be part of the Pharmaceutical Industry in India where the global generics market is considered the biggest opportunity for growth in the coming years. As many drugs lose patent protection and the local population gets better access to medicine the market is expected to grow substantially.

As more companies from India, China, Latin America and Central Europe compete for local market share, profits will be challenged. However, the local industry is well placed to respond; through consolidation and growth there are now three Indian companies in the Top 10 generic players, and another three global generic companies increasing their stake in India.

In 2010, the turnover of the Indian Pharmaceutical Industry was USD 13Bn, with an additional USD 8 Bn generated from exports. The Top 10 pharmaceutical companies in India generated more than 50% of their annual turnover from exports to over 100 countries. India also boasts of having the largest number of USFDA approved facilities outside the US. That number continues to rise, as Indian companies keep adding facilities to meet increased demand. Subodh says, “With the possibility of the Domestic Pharmaceutical Market reaching USD 70Bn by 2020, India will be one of the top 5 players in the world."

Speaking at the 63rd Indian Pharmaceutical Congress 2011 in Bangalore, Subodh, as President of the Indian Pharmaceutical Congress Association (IPCA), highlighted the opportunities, issues and challenges that lay in the industry’s path of growth. He commented that “India has every chance to capitalize on the opportunity to become a Pharmaceutical Superpower in 2020 and a significant hub for pharmaceutical manufacturing and research needs. With the majority of global companies now starting to outsource manufacture of intermediates, APIs & generic drugs, India is well positioned to compete and meet demand. The dream is to make India a hub for pharmaceutical manufacturing and research needs."

A recent study reported that, on an attractiveness index, India rated above average for technical capabilities and excellent for cost competitiveness; two of the most important factors for success in the generic market. India has easy availability to trained manpower; with 70% lower costs, compared to the US (Source: Ernst & Young). Setting up a FDA approved plant is 30% cheaper. Subodh explains, “These factors make the cost of manufacture lower than in the US and Europe, without compromising quality."

Subodh adds that, “Colorcon, with an experienced team in India, is well positioned to meet the current and future industry needs. They provide development and regulatory support to help customers meet the aggressive filing timelines demanded by the generics industry. Through training and continuous education, the team really understands customers’ challenges and needs; they are well organized and equipped to respond quickly with expert information and advice. Colorcon also has a leadership role supporting innovator companies, as well as emerging contract research organizations (CROs), as they transfer their production and R&D to India.”

Colorcon continues to invest in a strong and efficient local presence in India: delivering excellence in manufacturing, technical support, laboratory facilities and educational programs. Colorcon is well positioned to support the pharmaceutical industry towards “Vision 2020: India – The Pharmaceutical Powerhouse.

 HyperStart® Oral Solid Dose Starting 

 Formulation Service Made Easier than   


HyperStart® is a unique, confidential service based on Colorcon’s extensive know-how, to provide users with starting formulations for single unit and multiparticulate immediate, delayed and extended release drugs from solid oral dosages.

This service is available through a new on-line request form, located in the technical service area of our website. Once registered, customers can submit requests using a redesigned, easier to complete form. Customers can also check the status of their requests on the site.

HyperStart can reduce the time spent on initial formulation, helping to get your product to market faster.

Learn more about HyperStart, by clicking here and using your log-in to access the new form!


 Colorcon Adds Features to On-line
 Customer Services 

We are pleased to bring further enhancements to the customer login area of our website!

We hope you are finding this area of the website valuable and we welcome your feedback.

If you have not done so already, please visit our Services section to request access today!


 Technical Service Lab Relocation


Colorcon Completes Relocation of Technical Service Laboratory in Bologna, Italy

Colorcon is pleased to announce the opening of the new Technical Service Laboratory at the University of Bologna, Department of Pharmaceutical Science (Universita' di Bologna, Dipartimento di Scienze Farmaceutiche) in Bologna, IT.

This strategic relocation is designed to widen the technical support services available to Colorcon customers.

The facility opens on 9th May 2012; with the first event being the Colorcon Coating School®, given in Italian. Marcel Cimpan, Customer Care Manager, Colorcon Europe, who is well known to many customers in the region, will be present to officially open the laboratory on 9th May.

The move enables Colorcon, to work with a range of active pharmaceutical ingredients (API) with customers, while broadening the services and equipment available to them. The new facility also offers customers extended development support with core formulation and granulation applications, in addition to film coating.

To arrange a visit to the new laboratory, run lab-scale trials or secure your place for the Colorcon Coating School, please contact your local Colorcon representative.

Details of future events can also be found on our Educational Programs page.


 Colorcon® Educational Programs 2012


Colorcon continues to lead the industry with pharmaceutical training programs and seminars, bringing the latest information on formulation and coating technology.

Focusing on theory and practical application, the training programs provide pharmaceutical scientists with knowledge on the application and understanding of film coating, core formulation and/or modified release technology.

The industry renowned Colorcon Coating School® covers theoretical and practical aspects of current film coating technology, with laboratory and production scale coating. Course topics include the importance of tablet core design, best practice guides through optimization and validation, and on-going advancements in tablet coating formulation.

The Colorcon Formulation School® is now extended with specific programs on Fundamentals, Matrices, Multiparticulates and Osmotic Technology. With leading experts from industry, academia and Colorcon Technical Centers, the content delivers the formulations and processing essentials to save development time and support your first time right objectives.

With many companies looking to deliver modified release strategies, the Colorcon Modified Release Forum is a must to attend; bringing useful practical experience and extensive knowledge from key industry experts.

With Quality by Design (QbD) as a new featured topic, this event focuses on current and emerging technologies and challenges.

For more information and the 2012 schedule, visit our Educational Programs page!

 Regulatory Corner     

StarCap 1500®   Co-Processed Starch Excipient Receives Pharmaceutical Precedence of Use in European Union

StarCap 1500® a co-processed excipient, combining corn starch and pregelatinized starch, is designed specifically for use in pharmaceutical applications, such as tablets and capsules. Corn starch and partially pregelatinized starch are commonly used excipients in oral solid dosage forms. These components of StarCap 1500 meet the applicable compendial and regulatory requirements for the intended pharmaceutical uses in the United States, Europe, Japan and a number of other countries.

Recently, StarCap 1500 gained precedence of use within the European Union (EU) in an approved drug product. The product, 25 mg exemestane film coated tablet, was initially launched in Romania in 2010, then more broadly in the EU in 2011. StarCap 1500 is listed specifically in the ingredient list for the product. Details can be found (page 5) in the UK Public Assessment Record (UKPAR) linked to this product here.

With precedence of use in the EU, StarCap 1500 is now established as an approved excipient and can be used in drug products to be marketed within the EU. As detailed in the UKPAR listing above, each component of StarCap 1500 meets the appropriate compendia requirements. Colorcon's Global Regulatory Affairs Group can assist with technical, safety and regulatory information to support the use of StarCap 1500 in global drug applications within and outside the EU.

StarCap 1500 has also been included in approved drug products in a number of countries, in Latin America and Asia. Therefore, it is clear that pharmaceutical companies can confidently use StarCap 1500 in their formulation development, taking advantage of its unique functionality and improvements in flow, compressibility and pH independent release. StarCap 1500 is a product specifically designed for use in pharmaceutical tablet and capsule applications making this a good choice for formulators to improve formulations.


For more information on any products or services mentioned in this newsletter, please Contact Us!


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