Synchrotron
For the last 5 years, Improved Pharma has carried out a number of Synchrotron-based studies at Argonne National Laboratory, and especially beamlines 6-ID-D and 11-BM. Beamline 11-BM is optimized for powder diffraction analysis of crystals and formulations containing crystalline materials and beamline 6-ID-D is optimized for total scattering analysis of amorphous materials and formulations. Both of these beamlines are the best in the world or among the best two or three beamlines in the world for their particular analysis. Improved Pharma has the required arrangements with the US Department of Energy to use these facilities for proprietary measurements. Additionally, Improved Pharma has the proper agreements to carry out proprietary studies at the Industrial Pharmacy Services Laboratory and at charge-back X-ray diffraction, NMR, and porcine pharmacology centers at Purdue University. The COO of Improved Pharma is responsible for all studies and has access to consultants and technicians needed to carry out all of the studies in a highly accurate, professional manner.
Formulation
This section describes Improved Pharma’s offerings in two areas:
1. Synchrotron-based formulation design
2. Accelerated Formulation Development and Fast to IND (fIND)
Synchrotron-Based Formulation Design
Improper formulation selection or solid form selection can slow development and greatly increase costs. With the increased information Synchrotron-based studies provide, it is possible to greatly accelerate development by quickly finding the most stable and most soluble formulation.
· Formulations including improved formulations of existing products
o Improved Pharma uses its knowledge in solid-state chemistry and its access to Synchrotron facilities to design a solid form for formulation. In some cases Improved Pharma’s formulation design work will include the development of a preliminary IVIVC (in-vivo in-vitro correlation) dissolution test. Improved Pharma has extensive experience with amorphous formulations, spray drying, gel caps, SECs, coated particles, microencapsulation, roller compaction, granulation and other methods. Improved Pharma also has extensive experience with stabilizing unstable formulations. Improved Pharma can also resolve a wide range of formulation problems.
· Amorphous forms, polymorphs, solvates, salts, nanoparticles
o Utilizing Synchrotron-based analytical and pair distribution function data, Improved Pharma provides an expert assessment of the current status of your polymorph screening activities. These Synchrotron-based studies provide structural knowledge and also analytical information at/near the lowest possible detection limit. Improved Pharma may suggest additional experiments or approaches to determine which form is most stable. Improved Pharma can also use its superior expertise in solid state chemistry to design a solid form screening and selection process based on the structure and known properties of the starting drug. Finally, Improved Pharma can suggest when it is most appropriate to search for salts, cocrystals, or amorphous forms typically utilizing Synchrotron-based approaches
o Polymorphism and solid-state chemistry are the lynchpin in successful fast development. Improved Pharma uses its knowledge and expertise with Synchrotron-based data to get the solid-state chemistry right in a fast economical way. Thus stability, handling, and solubility problems are avoided and development is accelerated.
o Solubility – Getting the solid-state chemistry right is particularly important for poorly soluble compounds. For these materials, it is possible to gain substantial improvement in solubility by using the proper solid form – typically a salt, amorphous form or cocrystal. Additionally, materials milled to small particle size with surfactants provide another approach to enhancing solubility. Improved Pharma’s strategies are superior for poorly soluble compounds.
o Particle size – Improved Pharma has extensive experience with particle size issues and analytical methods to determine particle size. It is critical to understand particle size in the manufactured lot(s). Furthermore, in some cases, milling with surfactants is sufficient to achieve the desired solubility. Improved Pharma has the experience and knowledge to understand particle size effects on bioavailability and stability.
o An IVIVC or relationship can be extremely helpful in formulation design. Improved Pharma is capable of carrying out the screening experiments necessary to find a medium for an IVIVC, if possible. Improved Pharma could use dog or pig bioavailability data for these studies if requested.
Accelerated Formulation Development and Fast to IND (fIND)
Improved Pharma performs the following four steps to accelerate development of the best form and formulation.
1. Preformulation – Solid state chemistry and solid state properties
This step is key to finding the right form of your drug candidate. Improved Pharma helps you evaluate or discover new forms and select the best one for development. If needed, Improved Pharma can conduct a polymorph screen and determine the structure of the forms produced.
2. Amorphous screening or salt screening
If your molecule is poorly soluble Improved Pharma can perform amorphous screening and salt screening utilizing Synchrotron data to find the best form to take into the clinic and also the best form to insure good exposure in toxicology studies. Improved Pharma has high-level project directors who make sure the form chosen is the best for your particular needs.
Improved Pharma also selects the best formulation for the chosen form to ensure stability and good performance and verifies the stability of this form using structural information based on Synchrotron analysis and accelerated stability studies. Improved Pharma provides a protocol tailored to your specific needs.
3. Toxicity testing-Enhanced Exposure
Improved Pharma’s studies will lead to the best formulation for GLP studies and a method of testing using this formulation. Improved Pharma can arrange for GLP testing if required. Improved Pharma can avoid delays by close coordination with its closely linked GLP laboratories.
4. IND submission and GMP manufacturing
Improved Pharma’s studies will provide you with all of the information needed to manufacture Phase I supplies and can arrange for this manufacturing at a site nearby.
Thus, Improved Pharma has the skills and interest to work with you to make sure your molecule makes it to the clinic in an optimum formulation
Methods/Processes
Method development
· Improved Pharma’s access to beamline 11-BM at Argonne National Laboratory allows perhaps the most sensitive powder diffraction analysis in the world. This beamline has a 1-meter diameter diffractometer equipped with 12 analyzers offering the highest resolution in the Americas and among the highest resolution in the world. This capability means it is possible to detect even very weak diffraction lines form a range of contaminating crystalline materials. Through its collaboration with Excelsus, Improved Pharma is able to utilize sophisticated analytical algorithms to determine percentages of low concentrations of contaminants.Optimization of Spray Drying Methods
The levitated drop experiments outlined above are simulations of spray drying where the solvent evaporates from a droplet leaving a solid particle. Thus the translation from the levitated drop experiments to spray drying is expected to be routine in typical cases. Scale-up of manufacturing using spray drying is provided by Improved Pharma through its collaboration with the Purdue University Industrial Pharmacy Services Laboratory. The formulation is then hand filled into capsules for further study. If needed, GMP manufacturing can be provided in either the Purdue GMP Center or at the University of Minnesota GMP laboratory. In this way, formulations can be scaled up to prepare clinical supplies in a rapid, efficient manner.
A range of parameters needs to be controlled to optimize formulations prepared by spray drying. These parameters include solvent, polymer, polymer to drug ratio, salt formation, and the inclusion of surfactants. Typically, a design of experiments matrix is utilized to guide these experiments. Pair distribution function (PDF), stability, and/or dissolution profile are utilized to evaluate the various formulations. Improved pharma can provide a complete optimization study following these general procedures. The exact parameters optimized are determined on a case-by-case basis. Of particular interest is the utilization of salt-forming polymers to prepare especially stable formulations. Once the methods are optimized, they can be scaled up to prepare clinical supplies.
· Conversion of Spray Drying Formulations to Melt Extrusion
The conversion of spray dried methods to melt extrusion is possible especially if the structure of the spray dried formulation is understood as described above. Knowing the key structural parameters that need to be preserved in order to maintain optimum stability and optimum solubility/dissolution allows conversion of spray drying processes to melt extrusion processes.
Stability
Improved Pharma can carry out a range of accelerated and forced degradation studies. These studies focus on both chemical and physical stability of the solid form. Improved Pharma has a strategy using a minimum of experiments to obtain information on the stability of clinical supplies. These stability studies are used for a wide range of applications including selecting the best formulation and troubleshooting formulations problems.
Problem Solving
Improved Pharma provides a range of problem solving and information services based on the extensive experience of its scientists.
· Problem-solving
Improved Pharma has extensive experience solving stability, screening, crystallization, polymorphism, formulation and particle size problems. Improved Pharma prepares protocols to address these types of problems and has collectively over 60 years’ experience in working on these types of problems. Solving formulation problems is a particularly strong expertise of improved form as is solving crystallization and polymorphism problems.
· Intellectual Property
Improved Pharma has collectively over 38 years’ experience in intellectual property matters including litigation, providing scientific support for claims, reproduction of claimed procedures, and analysis of materials. Improved Pharma also has developed skills in strategy and approaches to innovation.
· Regulatory Information
Improved Pharma has collectively over 60 years of regulatory experience. Improved Pharma scientists have served on the USP, the FDA Pharmaceutical Sciences Advisory Committee, as special government employees for the FDA, and taught courses at the FDA as well as collaborated with the FDA to teach the first FDA course in Africa. Improved Pharma can provide specific information on development reports, quality overall summaries and methods development as well as more strategic regulatory reports.
· Short courses, Webinars, and Books
Improved Pharma provides a range of short courses and webinars based on the recently published book: Solid State Properties of Pharmaceutical Materials by Stephen R. Byrn, George Zografi, and Xiaoming (Sean) Chen, John Wiley, and Sons, Hoboken, NJ 2017. Improved Pharma can provide in-house short courses as well as webinars and on-line instruction.