Oral Solid Dosage I

Formulation Science - Solid Oral Dosage Form I

• Course: PR5217
• Instructor: Dun Jiangnan, Ph.D.
• University: National University of Singapore
• Semester: AY24/25.S1
• Date: 10-Oct-2024

Contact Information

• Email: [email protected]
• Office: S9 15-01F
• Office hours: By appointment only
• Response time: Typically 1-2 days; remind if not received
• Email questions: Limit to 3 per email

Learning Outcomes

• Understand the advantages of tablets
• Learn about common tablet excipients and their properties in solid formulations

Important Concept

• Pharmaceutics converts a drug into a medicine, and involves understanding physical chemistry, dosage form design, various manufacturing scales, and product performance testing.

Design of Solid Dosage Forms

• Preformulation Studies: Essential steps before formulation development to fully understand the physicochemical properties of drugs and other ingredients, and how they may interact in a dosage form. The data helps in designing the dosage form.
• Formulation: Involves understanding the small- and large-scale manufacturing, advantageous and disadvantageous properties of available dosage forms, and how modifying the properties of these forms relates to factors like administration route and patient needs.

Drugs in Solid State

• Drugs in solid-state can be administered as powders (e.g., metered-dose inhalers (MDIs)).
• Common solid oral dosage forms include tablets and capsules.

Learning Plan

• Week 8: Introduction to tablets.
• Week 9: Tablets II, and Capsules I; Quiz 1 (CANVAS)
• Week 12: Capsules II; Mini-Review; Quiz 2 (CANVAS)

Tablets

• 70% of drugs are administered orally in tablet form.
• Tablets are convenient, safe, robust, relatively inexpensive to mass-produce, and ensure quality and consistent preparation.
  • They offer advantages over liquid dosage forms in terms of chemical, physical, and microbiological stability.
  • They allow for precise dosing.

Types and Uses of Tablets

• Regular IR tablets: Immediate Release,
• Orally Disintegrating Tablets: Fast disintegration in mouth
• Chewable tablets: Designed for easy ingestion
• Modified Release tablets: Controlled release of the drug
• Sublingual/Buccal tablets: Under the tongue/cheek delivery, respectively.

Quality Attributes

• Critical Quality Attributes (CQAs) are characteristics impacting drug safety and efficacy.
  • Content Uniformity
  • Disintegration time
  • Tensile strength
  • Dissolution
  • Friability
• Necessary for the successful quality dosage form of a tablet.

Tableting R&D: Lab-scale Instrument

• Various lab-scale instruments including Zwick, Presster, and Styl'One are used in pre-formulation studies.

Manufacturing of Tablets: The Rotary Press

• Automated tablet presses are used for high-volume manufacturing.
  • Rotary press operation includes die filling, powder volume control, compaction, and tablet ejection stages

Toolings

• Different tooling shapes and designs are used to create tablets with various sizes, shapes, and markings, including break marks and symbols
  • Typical tablet shapes found include circular, oval, and oblong as well as triangular, or quadratic.

Tablets Formulation Development (3W)

• Drugs: What kind of drug? Considerations include preformulation (PR 5225)
• Excipients: What kind of excipients? The type and amount of excipients to consider in the formulations. This includes chemical nature, functionality, and quantity.
• Technologies: What kind of manufacturing technologies?

Example: A Standard IR Tablet Formulation - Materials/Quantities/Categories

• Provided data includes materials, quantities in mg, categories, and their functionality.

Filler/Diluent

• Excipients used to increase tablet volume/weight
• Overcome poor properties of API materials
• Critical properties: powder flow, tablet strength
• Desired Properties: uniformity, disintegration time, dissolution, friability, and physical/chemical stability.
  • Common examples: Lactose, Sucrose, Glucose, Mannitol, Sorbitol, Dicalcium phosphate dihydrate, Calcium carbonate, Cellulose.

Example 1: Microcrystalline Cellulose (MCC)

• Widely used as a filler in oral tablet formulations.
• Can also be used as a dry binder in granulation processes.
• Self-lubricated; low ejection force.
• Wood fiber, swells upon contact with water; can facilitate disintegration.

Crystalline and Amorphous Structure of Cellulose

• MCC isn't pure crystalline; includes amorphous regions.

Multiple Grades of MCC

• Different Avicel PH grades (PH 101, 102, 105, 200) have different primary particle size distributions and cohesive properties. (PH105 has the lowest primary particle size and highest cohesiveness).

Mechanical Properties of MCC

• Very plastic, readily deforms under low compaction pressure.
• Excellent mechanical properties; commonly used to overcome shortcomings in other drug compounds
• Sensitive to relative humidity (RH)

Selection of Excipient: MCC

• A guide to selecting the ideal MCC grade based on factors including batch size, nominal particle size, and moisture content.
• Various categories and properties highlighted.

Example 2: Lactose Monohydrate (LM)

• Primarily used as a filler/diluent in tablet formulations (e.g. Pharmatose 125M, SuperTab 30GR).
• Generally exhibits higher ejection force than MCC due to surface roughness.

Mechanical Properties of LM

• Manufactured in various grades, shapes, and surface properties.
• Unlike MCC, undergoes extensive fragmentation during powder compaction; creating new surfaces.

Lubricant: Magnesium Stearate (MgSt)

• Common tablet lubricant; high lubrication efficiency; economical.
• Forms physical layer on the tablet surface during manufacturing and ensures efficient flow and compaction.

Disadvantages of MgSt

• Diverse origins
• Hydrophobic
• Chemical impurities
• Phase impurities
• Poor flowability (cohesive)

MgSt may negatively impacts the MP

• This illustrates that the characteristics of MgSt can negatively influence other properties of the tablet. Specifically, it relates reducing friction but not necessarily increasing other properties like tensile strength.

Lubrication with MgSt Delays Tablet Dissolution

• Research articles on the effects of MgSt concentration on other aspects of the tablets.

Disintegrant/Superdisintegrant

• Added to ensure tablet breaks down in liquid.
  • Low rate of drug dissolution
  • Moderate rate of drug dissolution
  • Rapid rate of drug dissolution
  • Examples: Starch, cellulose, cross-linked polyvinylpyrrolidone (PVP), sodium starch glycolate, and sodium carboxymethylcellulose.

Glidant

• Improves powder flowability (e.g., Aerosil 200).
• Often added to granules before tableting to ensure even flow and mass achievement during high-speed manufacturing.
• Typically using <0.5% of a material like Aerosil 200.