Solid Oral Dosage Form II (PR5217) Formulation Science PDF

PR5217 Formulation Science L08 Solid Oral Dosage Form II DUN JIANGNAN, Ph.D. AY24/25.S1 17-OCT-2024 Learning Outcomes Understand the general formulation development stratergies in Direct compression. Understand the role of di erent drug loadings in the formulation development...

PR5217 Formulation Science L08 Solid Oral Dosage Form II DUN JIANGNAN, Ph.D. AY24/25.S1 17-OCT-2024 Learning Outcomes Understand the general formulation development stratergies in Direct compression. Understand the role of di erent drug loadings in the formulation development. Understand the common characterizations in tablet formulation developments. ff Direct Compression (DC) Simplest manufacturing technology for tablet. Mixing Compression Raw materials Blend Tablet product Pros Cons Simple Sensitive to material properties Economical Risky for high drug loading Risky for high potency drug formulation Goals of Formulation Development in DC Identify formulation composition Limited amount of API in early development (minimize the use of API) Identify a suitable manufacturing process Minimized formulation development time. Prioritize direct compression Identify characterization methods It is important to identify a reliable manufacturing process at lab scale, which can be scaled up in robust and predictable way into a rst clinical supply manufacture. fi Drug Loading Drug loading (DL), or dose strength, is a critical factor to consider during formulation design. Drug Loading Generally, drug loading in direct compression formulation can be catagroized as below: Less than 2% Between 2% to 5% Larger than 5% Development of multiple doses based on a “Dose-proportional” approach For example, commercial available Acetaminophen is available in 200, 400, 800mg. The formulation development of 400 mg and 800 mg can “copy” the formulation of 200mg. Less study is required Drug Loading Intrinsic API properties (physicochemical, mechanical, and bulk properties) are critical for any direct compression formulation. Depending on the DL, the major challenge during formulation/process design will be di erent: No more than 2% Between 2% to 5% More than 5% API Content Uniformity Final Blend Content Uniformity Tablets Mechanical properties Critical! FDA has very strict regulations on the uniformity of API distribution, as well as the manufactuirng process for low dose formulation. ff  DL < 2% DL Promising for high speed Foremost Fast Flo 316 36% Filler (brittle) manufacturing. Ac-Di-Sol 711 5% Superdisintegrant Magnesium Sterate 1% Lubricant Aside from traditional llers, some new excipients are used in modern platform formulations: Isomalt, SMCC (MCC+SiO2), CombiLac (MCC+LM+Starch), Sample platform formulation etc. ffi fi ffi  DL between 2% to 5% STEP 2 Testing for Excipient Compactibility In most of the time, the platform formulation is used for subsequent prototype screening; however, it is recommened that a minimum of 2-3 additional formulations are prepared at least for excipient compactibility studies. Components Percentag Function Components Percentag Function API e 4% API API e 4% API Pharmacel PH-102 54% Filler (plastic) SMCC HD90 54% Filler (plastic) SuperTab 11SD 36% Filler (brittle) Tabletose 80 36% Filler (brittle) GLYCOLYS 5% Superdisintegrant GLYCOLYS 5% Superdisintegrant Magnesium Sterate 1% Lubricant Magnesium Sterate 1% Lubricant Back up formulations are essentially platform formulations as well. They are being tested for excipient compactibility, so that we can con rm if the excipients proposed can be used as a back-up. fi DL between 2% to 5% STEP 3 Testing for Mechancial Properties Mechanical properties are characterized via compaction simulations Simulating multi-station tablet press in a lab setting Fundamental understanding of powder mechanical properties Predict compaction properties on a high speed production press (0.5 – 10g) Rotary press Compaction simulator DL between 2% to 5% Compaction simulation is a great way to eliminate surprises! Unpublished data DL between 2% to 5% STEP 3 Testing for Mechancial Properties Tablets are compressed under a various of chosen compaction pressure, leading to di erent tablets solid fraction (SF). Typically, a SF = 0.85 is the sweet point we would like to achive at the rst few trials. Creteria: Satis ed tabletability, fraibility, as well as manufacturability. A tablet with higher SF is denser compared with the one with lower SF. Thus, usually more stronger and exhibits longer disintegration time. SF = 0.90 SF =0.85 SF =0.80 Applying a larger compaction pressure is not neccessary increase the SF. Therefore, conducting compaction simulation is critical. fi fi ff Mechanical properties of Interests The mechanical strength of a tablet is associated with the resistance of the solid specimen to fracturing and attrition. Characterize the fundamental mechanical properties of materials used in tablet formulation. Assess the important formulation and production variables for the resistance of a tablet to fracturing and attrition during formulation work, process design, and scaling up; Control the quality of tablets during production. Tensile strength Hardness Friability Breaking force  Capping and Lamination The typical symptom of capping is the complete removal of top part of the tablet upon ejection or in subsequent handling and physical testing. A closely related tablet manufacturing problem is lamination, ranging from a presence of micro cracks visible on the side of a tablet to multiple separated layers Tablets with lamination defects do NOT exhibit tensile failure under the diametrical breaking test.  Capping and Lamination Material properties Starch is elastic Tablets made with starch is of higher MCC is plastic lamination tendency What do you think of ACM? Process parameters IER: In-die elastic recovery Increasing tableting speed -> less plastic Promotes capping and lamination deformation -> higher capping or lamination  DL between 2% to 5% STEP 4 Testing for Disintegration SF = 0.90 SF =0.85 SF =0.80 and Dissolution Tablets with di erent SF (around the target 0.85) are made from the main Disintegration Disintegration Disintegration platform formulation. Dissolution Dissolution Dissolution Absorption Absorption Absorption Content Uniformity Assay Accelerated Stability Test ff Dissolution Enhancement Solubility Surfaced Wetting Surface area Applying formulation technology Amorphous solid dispersion Replacing hydrophobic excipient with more hydrophilic one MgSt-alternative lubricant: Sodium Lauryl Sulfate (SLS), Poloxamers (P188, P407) Decreasing the particle size of DS Usually not favorable after Phase I In the stomach, we already had a variety of surfactants, Adding surfactant in the formulation why do we need to add more in the formulation? Hydrophilic surface coating  Surface Wetting: The Contact Angle Forming contact angle is a surface phenomenon Contact Angle Goniometer When a solid surface comes in contact with a liquid, the complex e ects of the surface morphology (roughness), its chemical composition, and the short- and Tablet surface must be at long-range intermolecular forces developing with the liquid (vdW, H polar bonding, electrostatic attractions with lone electrons pairs, etc…) determine an Minimizing the vaporation of water equilibrium condition in which the surface may or may not be wetted by the liquid, depending on how much favorable the interactions between the two are. fl ff  Formulation Strategies: Wettability A high surface wettability enhances the tablet dissolution SLS is more hydrophilic than MgSt, and exhibits smaller contact angle Superhydrophobic PVP coating could change the contact angle of silica  DL between 2% to 5% STEP 5 Testing for Punch Sticking This is typically the last step before a nal formulation prototype is selected. Punch sticking refers to the adherence of the powder material onto the tooling surface during compaction of tablets. Punch sticking is usually identi ed in the late stage of formulation development. 1. Compromised tablet quality 2. Loss in manufacturing e ciency (clean punch head) Severe sticking 3. Increase cost (change formulation) Mild sticking (Punch surface) (Punch surface + tablet Paul et al, 2017, J. Pharm. Sci. 106:151-158 picking) ffi fi fi  Origination of Punch Sticking Poor physicochemical and mechanical properties of materials Sticking investigated across 24 compounds (excipients and APIs) (1) For some materials, the sticking process reaches a saturation point at an in nite number of compressions, but the maximum amount of sticking di ers for di erent compounds. (2) It is important to note that compounds with high sticking propensity (>800 μg after 100 compaction runs) tend to maintain linearity through a signi cantly larger number of compactions than compounds that are not very sticky (100-300 μg after 100 compaction runs). Paul et al, 2017, J. Pharm. Sci. 106:151-158 fi ff ff fi  Punch Sticking Model F1> F3 >F2, API adheres to punch surface to form a monolayer but continuous buildup of API layer does not occur. Tablets compressed with lmed punches are usually dull, instead of having a more appealing shining appearance. Sticking curves corresponding to type I behaviors level o at a low level of mass sticking to the punch tip, suggesting monolayer coverage by API. F1 > F2 ≥ F3, API-API cohesion is greater than the adhesion between API and the tablet matrix. As the compression proceeds, the API layer on the punch will grow thicker. This corresponds to the severe case of punch sticking, which always requires stoppage of compression process for punch F1 (Punch-API Adhesion) cleaning. Dislodging of the adhered material can occur, but practically rare F2 (API-API cohesion) seen. Why? F3 (Excipient-API Adhesion) Glidant Paul et al, 2017, J. Pharm. Sci. 106:151-158 fi ff DL > 5% Unlike low and extremely low drug loading formulations, when the target drug loading is higher than 5%, the main challenge shifts to the mechancial properties and manufacturability. Now, here is a major question before we can further proceed: What would be the highest possible DL? OMG, this is a simple question, but not so simple to answer in most of the time… Typically, DL exceeds a max of 60% is not considered to be suitable for direct compression. Therefore, 60% is a good starting point unless formulator obtained more information to narrow down the number. DL > 5% STEP 1. Identify the maximum possible DL When DL increases, powder owability generally decreases (sharply), due to the poor ow properties in API(High surface roughness, small mean particle size, as well as iiregular particle shapes). Thus, measuring the ow of nal blends with various of DL is a good stratergy to identify the Max DL. Angle of Repose Ring Shear Cell Tester (key parameter: c) fl fi fl ff fl  DL > 5% Formulations with 60% DL Prepared by V Blender or Turbula STEP 1. Identify the maximum possible DL Conducted under various of Ring Shear Cell Tests normal forces (mimic storage conditions in hopper) Satis ed FFC (at least 6) Pass Wall Friction Tests Hopper design Identi ed the Max DL fi fi  DL > 5% STEP 1. Identify the maximum possible DL The ratio of selected llers remains unchanged (platform formulation approaches) during DL Unatis ed FFC (< 6) dilution process. The process will continue, usually in a 5% interval, until the measured FFC satis es the Dilution of DL mimimum requirement (i.e., FFC = 6) Satis ed FFC (at least 6) Identi ed the Max DL fi fi fi fi fi  DL > 5% STEP 1. Identify the maximum possible DL Unatis ed FFC (< 6) If the formulation has been diluted multiple times, yet to satisfy minimum FFC requirement. A brand new formulation with di erent sets of excipients are required to proceed further. Dilution of DL The backup formulations can be used in this case. How do you know the minimum DL you can dilute your Satis ed FFC (at least 6) formulation to? fi fi ff DL > 5% STEP 2. Prototype selection based on the identi ed Max DL This step is similar to the one that was explained before, except that a range of DL is investigated to give formulator a broad picture of the mechancial properties. API (mg) 5 6 7 8 9 10 Total Tablet 100 100 100 100 100 100 weight (mg) DL 5% 6% 7% 8% 9% 10% Non-Linear Dose Design fi DL > 5% STEP 2. Prototype selection based on the identi ed Max DL This step is similar to the one that was explained before, except that a range of DL is investigated to give formulator a broad picture of the mechancial properties. API (mg) 40 50 60 70 80 90 Total Tablet 133.3 166.7 200 233.3 266.7 300 weight (mg) DL 30% 30% 30% 30% 30% 30% Linear Dose Design (preferred) fi End of the Session