Q&A: Formulation Considerations for development of Ternary Solid Dispersions

Dr. Harsh Chauhan, Creighton University

Q: What do you mean by precipitation of indomethacin? The objective not clear and what is the inference of this.
A: Precipitation of indomethacin is referred to as pure indomethacin precipitation when its added to phosphate buffer. The study is used as control i.e. precipitation of indomethacin in absence of polymer.

Q: Is there a possibility to quantify the % of the drug interacted with each polymer in TSD. for example the IND-PVP-Eudragit E system.
A: It can be but not by using IR/ Raman techniques, we used. The peak shifts were very small and were not concentration dependent. Techniques like ssNMR, solution based techniques might be used to quantify the interactions. 

Q: What cooling rate do you use for the crystallization tendency experiments?
A: We used 2-5C/ minutes as our cooling rate for crystallization tendency experiments. 

Q: When you talk about precipitation inhibition, with the ternary system, do you get clear solution or colloidal solution? How you corelate the in-vitro solution behavior with in-vivo drug absorption?
A:
We got clear solutions but after precipitation it turned into a coarse dispersion. We didn’t carried out in-vivo drug absorption experiments. 

Q: Did you perform your DSC data on physical mixtures or did you process them in advance? Nucleation is more likely in physical mixtures than in homgeneously dispersed systems.
A:
For crystallization tendency and miscibility studies we used physical mixtures in various heat-cool-heat cycles. We also characterized dispersions for Tg, crystallization, any other endothermic-exothermic events.  

Q: On slide 30, how do you untangle the observation of crystallization during the evaporation step from acetone from the stabilization offered by the hydrophilic polymer. nucleation could be happening purely from the evaporation of acetone.
A: Agreed. We wanted to study the crystallization (nucleation) in absence and presence of polymers. We wanted to explore the feasibility of using it as quick study to identify polymers inhibiting drug nucleation.

Q: Are there any compound characteristics which make it impossible to stabilize in amorphous form using ternary dispersions?
A: There are no specific characteristics but sometimes achieving the correct balance in terms of solubility and stability increase is difficult. We have observed good long term stability of certain compounds but unfortunately the solubility increase was not sufficient despite >90% polymer concentration.

Q: Indomethacin has been tried in many classical ways like solid dispersion, etc .. what is the difference and significance of doing the same old drug in improving the solubility and of course bioavailability?
A: Indomethacin was used as a model compound. We prepared anti-tubercular/ anti-cancer combinations base don our understanding of indomethacin system.

Q: Can the effect of adding a third component on drug-polymer interaction and hence the stability of the Binary ASD be predicted?
A: Yes, the effect can be because of drug-polymer interactions but its difficult to predict. We have limited success based on various interaction parameters. It will be a great next step for the ternary systems if we can predict.

Q: Can you tell us something about the PEG Dispersions and the stability related issues?
A: We did very limited studies on PEG based dispersions and mostly used it as a control. Since, PEG is a crystalline polymer with low melting point (60C or so), the dispersions were difficult to characterized as amorphous. We observed crystalline peaks and for the drugs we used it was not stable (amorphous form). However, PEG can be a good polymer for creating eutectic, nono-crystalline/ molecularly dispersed drug in crystalline matrix.

Q: Are there any commercial products in market utilizing ternary polymer amorphous dispersion approach?
A: No, but there are few systems in clinical trials.

Q: So does molecular modeling predict tractable polymers for specific drugs?
A: We use molecular modeling in conjunction with other miscibility/ precipitation studies to better select most optimum polymer. In our experience, molecular modeling alone cant be used to accurately predict most optimum polymer for specific drugs. 

Q: How do you test miscibility in the ternary system? You are right about the lack of predictability of theoretical models. Then, how do you ensure that the drug will not crystallize out upon long-term stability?
A: Melting point depression, drug crystallization tendency, miscibility studies using MDSC can be used to give some insight into long term stability. If we have low drug loading and if polymer showed strong interactions with the drug, the system can be assumed to pose no stability challenges. However, actual studies or accelerated studies are required to confirm.  

Q: With ASD, what is the max oral dosing that has been achieved for BCS class IV drugs?
A: We are not aware of max oral dosing for Class IV drugs. Our studies have mostly focused on Class II drugs.

Q: You mentioned during your talk that in the case of BCS IV drugs, Amorphous Solid Dispersions affect only solubility, not permeability which is mediated by P-glycoprotein (P-gp). However, surfactants and polymers in Amorphous Solid Dispersions have been reported to inhibit P-gp in vitro. Please elaborate. Thanks.
A: You are correct. I don’t recall making the statement but its wrong. Appropriate polymers and surfactant can affect both solubility and permeability.

Q: What are the main mechanisms by which a good “parachute” phase can be achieved?
A: Polymers effect on crystal growth, high molecular weight, stronger interactions between drug and polymer are some of the mechanism for a good parachute.

Q: Have you tried any high Tg lipids >50C and formualted into successful ASDs?
A: No, we haven’t tried high Tg lipids.

Q: How can we quickly scan the most appropriate drug-polymer-surfactant with so many polymer or surfactant options without large scale manufacturing? Have you tried any high throughput methods?
A:
Yes, we have tried precipitation studies in a 96 well plate and thin film casting method with good success to identify most appropriate polymers/ surfactants.

Q: XRD studies also to be performed simultaneously with DSC… to find the thermodynamic stability… But how best we perform stability studies. And is a 3 month study sufficient?
A:
Usually, 3 months studies are no sufficient. Accelerated stability studies at high RH and T are recommended. Personally, I will recommend carrying out at least XRD, DSC and in-vitro release studies throughout the stability testing to assure of good stability and performance. During initial ASD development for animal tox studies/ preformulations stages 15 days-3 months studies are usually sufficient.

Q: Is hot stage microscopic evaluation will give any useful information on ternary solid dispersion? considering individual melting points by polymers and drug substance?
A:
Unfortunately, not. Tg/ Tm of one component will affect the subsequent Tm and it will be difficult to get any quantitative information.

Q: Have you tried using drug- polymer lipid – combination as amorphous solid dispersion approach for enhancing bioavailability and stability?
A:
We tried a few combination but stability was a concern due to low Tm of lipids.

Q: Is there a possibility to quantify the % of the drug interacted with each polymer in TSD. For example, the IND-PVP-Eudragit E system.
A:
It will be difficult but ssNMR can be tried. We tried using IR/ Raman but getting quantifiable interactions was difficult.

Q: You mentioned during your talk that in the case of BCS IV drugs, Amorphous Solid Dispersions affect only solubility, not permeability which is mediated by P-glycoprotein (P-gp). However, surfactants and polymers in Amorphous Solid Dispersions have been reported to inhibit P-gp in vitro. Please elaborate.
A:
You are correct. I don’t recall making the statement but its wrong. Appropriate polymers and surfactant can affect both solubility and permeability.

Q: What is the relationship between solid dispersion and bioavailability?
A:
Solid dispersion is an approach to enhance solubility leading to higher bioavailability of poorly soluble compounds.

David Preston
David Preston

Chairman

David Preston has had 38 years of healthcare experience with publicky Traded and Private companies in the fields of Phammaceuticals, Animal Health and Biotechnology as a Board Member. The last 30 years of his xperience has been in China, Taiwan and Hong Kong building successful igh growth businesses. David Has been Chaiman and CEO for Greater China for Sanofi and Boehringer – Ingelheim as well as the Janssen Corporation since 1991 in China. During this time he build high Growth ousinesses in China through diversified strategies in Innovative Pharmaceuticals. branded Generics. Biotechnology. and Animal Healthcare.

Key highlights in this period indluded building of the first Westem Multinational Biotechnoloqy C.M.O. facility as well as obtaining the first Test CM.OJ MAHI license. Establishment of a number of High tech Vaccine Plants, and R and D facilities in in the field of Animal Health. Signing and development of numerous JV’s as well as Wholly owned Subsidiaries. Mergers and Acquisitions across Phamaceutical’s. Animal Health. and Biotechnology industries

David’s achievement’s in the Healthcare industry and it Growth and development in China is widely recognized By the Chinese Govemnment and the City of Shanghai In 2013 he was awarded the Silver Magnolia ollowed in 2015 the Gold Magnolia award. This was then followed by being awarded in 2017 the Honorary Citizen of Shanghai by 40th People’s Municipal Congress of Shanghai. David Holds a Business Science Degree

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Filippo
Filippo de Vecchi

Director, Advent Partner

Filippo de Vecchi joined Advent in February 2000. He started in the Advent São Paulo office, then moved to Milan in 2002, in 2012 set up the Advent office in Shanghai and in 2016 set up the Hong Kong office. Before joining Advent, he was a senior consultant with Value Partners, in São Paulo and Milan, focusing on strategy and organization in the automotive, energy, cable and media sectors. He began his career at Wasserstein Perella & Co., working as an analyst in the Mergers and Acquisitions department in London and New York. Filippo holds an undergraduate degree cum laude in Economics, with a major in Business Administration, from the LUISS University and an MBA from Columbia Business School, where he currently serves as a member of the Board of Overseers.

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Andrew Li
Andrew Li

Director, Advent Partner

Andrew Li joined Advent in 2012. He previously worked at Warburg Pincus, HSBC PE, Solera Capital and Credit Suisse where he focused on the retail and consumer, healthcare, industrial, and energy sectors. Andrew has worked in finance and private equity throughout the U.S. and China since 1999. Andrew holds a BA from Middlebury College and an MBA from Harvard Business School.    

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Michael Miltenberger
Michael Miltenberger

Director, Advent Partner

Michael Miltenberger  joined Advent in 2011 as an associate on the healthcare team. Following business school, he rejoined Advent’s Boston office, focusing on healthcare investments. Prior to Advent, Michael was a consultant at McKinsey & Company in their Washington DC office, serving a range of healthcare and private equity clients. Michael earned a BA, cum laude, from Harvard College and an MBA from Harvard Business School, graduating with High Distinction as a Baker Scholar and a Harvey Fellow.

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Masood Tayebi
Masood Tayebi, PhD

Director, Operating Partner

Dr. Masood Tayebi is the Founder of BioDuro. He currently serves as CEO of a nationwide real estate portfolio and is a Partner and Chief Executive Officer of the Bridgewest Group. Prior to BioDuro, Dr. Tayebi was Co-Founder and Chairman of Wireless Facilities, Inc. (NASDAQ: WFI), a global leader in telecommunications outsourcing.

Achievements
  • Co-Founder of Wireless Facilities, Inc.

  • Co-Founder of BioAtla, LLC

  • Recipient of the Ernst and Young 2000 Entrepreneur of the Year award in San Diego

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Kewen Jin
Kewen Jin, PhD

Director, Operating Partner

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Amit patel
Amit Patel

Director, Operating Partner

Amit Patel has twenty years of healthcare industry experience with publicly-traded, private equity-backed, and start-up companies in the capacity of executive, board member, advisor, and investor.  He is currently Executive Chairman of Azurity Pharmaceuticals (a NovaQuest Capital Management portfolio company) and a board member at BioDuro (Advent International portfolio company), Tergus Pharma (Great Point Partners portfolio company) and Calyptus Pharma.  Recently, Amit was SVP & President of Dosage Form Solutions at Capsugel, a KKR portfolio company (purchased from Pfizer in 2011 and sold to Lonza in 2017).   

Prior to Capsugel, he worked at Dr. Reddy’s Laboratories, Inc. as EVP & Head of North America, and SVP & Head of Global Corporate Development & Strategic Planning. Earlier, Amit was VP of Corporate Development at CTIS, Inc., and Co-founder & CEO of MedOnTime, Inc. (acquired by CTIS).  He started his career as a strategy consultant with Marakon Associates. Amit holds an M.B.A. degree from Harvard Business School, a B.S. degree in Economics from the Wharton School of Business, University of Pennsylvania, and a B.A.S. degree in Systems Engineering from the Moore School of Engineering, University of Pennsylvania.

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Haijun Dong
Haijun Dong

Chief Executive Officer

Dr. Haijun Dong currently serves as global CEO of BioDuro-Sundia. He previously was CEO for over 5 years at PharmaBlock Sciences Inc., a public company listed in the Shenzhen Stock Exchange (300725.SZ). The positions he held prior to PharmaBlock includes, among others, Senior Scientist at Boehringer Ingelheim Pharmaceuticals in Ridgefield, Connecticut; Senior Principal Scientist at Roche in Nutley, New Jersey; Head of DMPK and Drug Safety at Roche China R&D Company in Shanghai; Chief Operating Officer of Eli Lilly China R&D Center in Shanghai.

Dr. Dong received his PhD in organic chemistry from the University of Washington in Seattle, Washington, and MBA from China Europe International Business School in Shanghai. 

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Teo Nee Chuan
Teo Nee Chuan

Chief Financial Officer

Teo Nee Chuan joined us in May 2021 as chief financial officer. Prior to joining us, he was chief financial officer of Huazhu Group from November 2015 to May 2021, and was the chief financial officer for Rnomac International Limited, from November 2011 to August 2015. Mr. Teo worked in DDB Greater China Group, was appointed as the chief financial officer in September 2009, and was additionally appointed as the director of operations in January 2011. He previously served in Focus Media Group and was appointed as the financial deputy director in June 2007. Prior to that, from September 1994 to May 2007, Mr. Teo worked at Ernst & Young and Ernst & Young Business Services Ltd. in various positions in Kuala Lumpur and Toronto, including as a senior manager in the Transaction Advisory Services. Mr. Teo has been an independent director of 111, Inc. (a company listed on the NASDAQ, ticker symbol: YI) since September 2018. Mr. Teo received his Bachelor of Science in Accounting and Financial Analysis degree from The University of Warwick in the United Kingdom in July 1994. He is a Chartered Certified Accountant in the United Kingdom, who has obtained his qualification in July 1998 from The Association of Chartered Certified Accountants, and is a Certified Public Accountant in the United States and Hong Kong, who has obtained his qualification from American Institute of Certified Public Accountants in May 2002 and Hong Kong Society of Accountants in October 2003, respectively.

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TJ
TJ Deng, PhD

President, Discovery

Dr TJ Deng joined BioDuro in the initial stages of the company and helped BioDuro grow to an industry leading discovery services organization. He established and managed several scientific departments, including DMPK, before transitioning to a leader of the business and operations functions. Prior to joining BioDuro, Dr. Deng spent six years at PPD, in positions with increasing responsibilities from scientist to scientific manager.

Achievements

 

 

  • Developed the extractable/leachable capabilities at PPD
  • 18 years industry experience

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Kent Payne
Kent M. Payne, PhD

Chief Executive Officer

Kent is distinguished as a business operator and leader in areas of sales, commercial manufacturing and product development. He has extensive executive experience in M&A as well as successfully running, start up, growth and turn around businesses. This includes both Fortune 500 and Private Equity environments. He combines strong business leadership, successful P&L track record, and technical background to strategically lead and grow enterprise value across Biotechnology and Pharmaceutical market segments. He has successfully led the geographic expansion of businesses into Europe, Asia, and South America in addition to the United States.  He currently serves as CEO for BioDuro-Sundia, LLC (an Advent International company). He also currently serves as a board member for Goodwin Biotechnologies (a Signet Healthcare company). 

Prior Roles

  • President, Global CMC Solutions BioDuro-Sundia, a global
    CRDMO
  • CEO Socorro Pharmaceuticals, LLC, a generic pharmaceutical
    company
  • President Americas, Qualicaps Inc.(a Mitsubishi Chemical Holdings subsidiary)
  • Principal Consultant and Partner at CoreFactor LLC, providing executive strategic, licensing and operational advisory services to clients.
  • Vice President/General Manager Catalent Pharma Solutions, Inc. (a Blackstone Group company formed in 2007, formerly part of Cardinal Health)
  • Progressive leadership responsibility at: Novartis, Monsanto and G.D. Searle.  

Prior Brand Position

  • Board Advisor Vitruvias Therapeutics
  • Board Member Qualicaps, Inc. (a wholly owned subsidiary of
    Mitsubishi Chemical Holdings)
  • Board member Technophar, Inc. (a wholly owned subsidiary of
    Mitsubishi Chemical Holdings)
  • Board Advisor, Corporate Strategy Office, Life Science Institute
    Inc. (a wholly owned subsidiary of Mitsubishi Chemical Holdings)
  • Non-executive Chair and Board Member PDS Biotechnology·        (PDSB: NASDAQ)

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John Phillips
John Phillips

Vice President, Business Development (US & EU)

Coming soon…

Achievements

 

  • Coming soon…

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Roy Xu
Roy Xu

Chief Strategy Officer

Roy has over 25 years of healthcare industry experience.  He started his career as an orthopedic surgeon.  Roy joined Eli Lilly as a sales rep in 1997.  Since then he has had various roles in market research, business intelligence, BU head, strategy, regional general management, business development etc., both at Eli Lilly and Boehringer Ingelheim (BI).  Roy also spent more than two years in Germany where he was BI’s Director of Corporate Business and Enabling Strategy.

Roy obtained a bachelor’s degree in Clinical Medicine at Zhejiang Traditional Chinese Medicine University, and an MBA from Zhejiang University.

Achievements

 

  • 25 years of healthcare industry experience including Eli Lily and Boehringer Ingelheim. 
  • Former Director of Corporate Business & Enabling Strategy at oehringer Ingelheim in Germany.

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San Diego

BioDuro- San Diego Facility

Our San Diego site is our corporate headquarters. The facility is home to BioDuro-Sundia’s drug product development technologies and has 9 GMP clean rooms. Development and manufacturing operations are conducted for projects up to Phase III clinical trials.

Size: 44,000 sq. ft.
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CA 92121
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Beijing

BioDuro Beijing

Operating since 2006, our Beijing site is home to BioDuro-Sundia’s first wet chemistry operations. With 300 regular fume hoods and 18 scale-up chemistry hoods the Beijing facility houses most of BioDuro’s chemistry operations, while also hosting labs for biology and monoclonal antibody discovery.

Size: 100,000 sq. ft. 
Featured capabilities: Radioactivity Lab, Monoclonal Antibody Discovery, Medicinal Chemistry

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Changping District Beijing,
102206
P.R. China

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Shanghai-Waigaoqiao

BioDuro- Shanghai Facility

Established in 2012, BioDuro-Sundia’s Shanghai facility has been growing with its departments. The cutting edge facility contains labs for ADME, bioanalysis, in vitro assays and translational research. The site includes a 18,000 sq. ft vivarium and 20,000 sq. ft of office space.

Size: 92,000 sq. ft.
Featured capabilities: Scale-up Chemistry, Discovery Biology, DMPK, In Vivo Pharmacology

No. 233 North Fu Te Road
Waigaoqiao Free Trade Zone
Shanghai, 200131
P.R. China

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Cathy Yen
Cathy Yen

Director, Operating Partner

Cathy joined the Board of Directors of BioDuro-Sundia in 2020, with the Advent-led acquisition of Sundia and creation of BioDuro-Sundia. Prior to that, she was Chairman of the Board at Sundia Meditech Group, where she was the key architect of Sundia’s strategic vision and growth. Under her leadership, Sundia solidified its position as one of the leading pre-clinical CROs in China.

Prior to Sundia, Cathy had a distinguished career as a seasoned venture capitalist, having led numerous investments in high-growth companies in Asia. Cathy served as a Partner of AsiaVest Partners, TCW/YFY Ltd., a global venture capital firm, for over a decade, Vice President at Global Financial Services, Vice President at Crimson Ventures/Chinatrust Bank and Senior Manager at Fortune Capital. She brings over 20 years of experience in corporate finance, accounting, strategic planning and private equity investments. 

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Wuxi

Wuxi - BioDuro

Established in 2019, BioDuro-Sundia’s fully integrated discovery facility located at the heart of Jiangsu Wuxi Life Science & Technology Industrial Park with plans of growing staff to 1000+ scientists.

Size: 300,000 sq. ft.
Featured capabilities:
Discovery Chemistry & Biologics, Biology, DMPK, Pharmacology, CMC Services

no.1699,Huishan avenue
Huishan Economic 
Development Zone,Wuxi
P.R. China

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Hebei

Hebei - Sundia

Established in 2011, this pilot plant this handles mg to kg scale up.

Size: 45,208 sq. ft.

Featured capabilities: SFFS Chemistry: mg to kg scale up
(150 hood)

238 Changjiang Road
Shijiazhuang,
Hebei province
P.R. China

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Taiwan

Taiwan Sundia

Our site in Taiwan supports Discovery Biology and Chemistry.

Size: 3,352sq.ft.
Featured capabilities: Chemistry;Biology

7F, No. 107, Sec. 4
Ren Ai Road,
Da-an District,
Taipei, Taiwan

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Bengbu

Bengbu - Sundia

Scheduled to open in fall of 2021, this site is designed to handle non-GMP manufacturing, advanced intermediates, GMP starting material(RSM) for IND enabling sttudies as well as clinical and commercial use. 

Size: 43,056 sq. ft.
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Mohekou Industrial Park,
Huaishang District, Bengbu, 
Anhui province
P.R. China

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Shanghai-Changli

Shanghai Changli

Our Shanghai-Changli site supports FTE cheimistry and advanced Discovery Chemistry processes.

Size: 71,844 sq. ft.
Featured capabilities: Chiral Analytical Lab, Analytical and Purification Lab, NMR Lab, Synthetic Lab, Parallel Synthesis Lab, Flash Chromatography Lab..(380 hoods)

法拉第路251号8号楼;
Building 8, 251 Faladi Road,
Zhangjiang Hi-Tech Park,
Shanghai, China
P.R. China

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Shanghai-Halei

Shanghai Halei

Opened in 2018, BioDuro-Sundia’s Shanghai-Halei contains facilities that support both Discovery and CMC parts of the drug development & manufacturing process. Facilities include amorphous dispersion techniques like SDD & Discovery Biology.

Size: 31,043 sq. ft.

Featured capabilities: Formulation : Preformulation, Wet Granulation, Compression, Tablet Coating, Fluid Bed Room, Spray Dryer, Hot Melt Extrusion, Dry Granulation Biology: Kinase selectivity, Cellular Assay, Compound Screen, Immune oncology service

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Zhangjiang Hi-Tech Park,
Shanghai, China

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