07 LIQUID

Manufacturing Liquid Drug Delivery System

Liquid Dosage Forms

  • BIOGESIC Anak

  • BIOGESIC Anak Solutions

  • Suspensions

  • PROPOFOL INJECTABLE EMULSION 1%

    • Administration: 200 mg/20 mL (10 mg/mL)

    • Contains Benzyl Alcohol

    • Starting: Nonpyrogenic

    • Instructions: Shake well before use

    • Rx Only

    • Emulsions

Solutions

  • Solutions: Two or more substances mixed homogeneously

  • Most common liquid dosage form

Water in Manufacturing Solutions

  • Question: What type of water should we use for manufacturing solutions?

  • Types of Aqueous Solvents:

    • Purified Water

    • Water for Injection

    • Sterile Water for Injection

    • Bacteriostatic Water for Injection

  • Production Methods: Distillation, Reverse Osmosis, Ion-exchange

  • Purified water required to be pyrogen-free

  • Sterile water used, packed in single-dose containers or with bacteriostatic agents in multiple-dose containers

Requirements for Solutions

  • Must be free from:

    • Impurities

    • Coliform bacteria

    • Manganese, Iron, Silicon, Bicarbonate, Sulfate, Sodium, Chlorine, Magnesium, Calcium

Selection of Solvent

  • Factors to consider:

    • Clarity

    • Low toxicity

    • Viscosity

    • Compatibility with other ingredients

    • Chemical inertness

    • Palatability

    • Color & Odor

    • Economy

Excipients in Solutions

  • TABLE 1: Pharmaceutical Excipient Purposes

    • Protecting Active Product Ingredients: Buffers, Antioxidants, Preservatives

    • Maintaining Appearance: Colorings, Stabilizers, Cosolvents, Antimicrobial Preservatives, Electrolytes

    • Taste/Small Masking: Sweeteners, Flavorings

Co-solvents

  • Co-solvents: Water miscible solvent enhancing drug solubility

    • Common examples: Ethanol, Sorbitol, Glycerin, PG, PEG polymer

Solubilizers

  • Use of surfactants to form colloidal aggregates (micelles)

    • Examples include Polyoxyethylene and Fatty acid esters (Tween series)

Buffers and pH Adjusters

  • pH selection is crucial for solubility and stability (commonly pH 4-7)

  • Common agents: Citric, Glutaric, Lactic acid

Preservatives

  • Preservatives must be effective against: microorganisms, oxidation, and hydrolysis

  • Non-toxic and non-sensitizing

Classification of Preservatives

  • Types:

    • Acidic

    • Neutral

    • Mercurial

    • Quaternary Ammonium Compounds

    • Phenol

    • Alkyl esters of parahydroxybenzoic acid

Sweetening Agents

  • Combinations of sucrose and synthetic sweeteners to mask taste

    • Common examples: Aspartame, Sorbitol

Viscosity Controllers

  • Improve palatability and pourability by controlling viscosity

    • Examples: PVP or cellulose derivatives

Flavor and Colorants in Solutions

  • Flavoring: Oil-based flavors require co-solvents; Natural flavors may precipitate with alcohol

  • Colorants: Should be consistent with flavor

General Steps in Manufacturing Pharmaceutical Solutions

  1. Preparation of solvent materials and containers

  2. Compounding

  3. Storing and Aging

  4. Clarification

  5. Filling and Packaging

Compounding Process

  • Raw Materials should meet specifications for ID, purity, uniformity, and microbial contamination

  • Necessary Equipment: Mixing tank, filtration system, and Cleaning methods

Equipment for Mixing

  • Mixing Tank:

    • Made of polished stainless steel for sanitation

    • Two grades: SS304 and SS316 (most inert, high grade)

    • Typically jacketed for heating or cooling

Mixing Techniques

  • Fluid Mixing: Involves continuous phases (fluids)

  • Single-Phase Mixing: Miscible liquids

  • Multiphase Mixing: Involves mixing of immiscible phases

Importance of Mixing

  • Required for rapid homogenization and intimate contact between phases

  • Commonly used in pharmaceutical processes

Baffles in Mixing

  • Added to prevent vortex formation in mixing tanks, particularly in turbulent flows.

    • Typically four baffles are used to improve mixing efficiency and prevent stagnation

Impellers in Mixing

  • Radial Impellers: Pump radially and are used mainly for low-viscosity liquids

  • Axial Impellers: Primarily pump vertically for efficient mixing of low viscosity liquids

High-Shear Mixing Equipment

  • Generates high velocity gradients across small areas

  • Used to disperse or homogenize immiscible phases effectively

Filtration Systems

  • Classified by:

    • Driving force: Gravity, pressure, centrifugal, vacuum

    • Method of operation: Batch or continuous

    • Desired end-product: Filtrate or residue

Filling Methods for Solutions

  • Gravimetric: For large containers; especially viscous liquids

  • Volumetric: Employs positive displacement of piston action to ensure constant volume

Suspension Overview

  • Suspensions: Dispersion of an internal phase in an external phase, can be colloidal or coarse based on particle size

  • Uses: Administer insoluble compounds, improve drug stability, and mask unpleasant tastes.

Ideal Properties of Suspension

  • Must have uniform dispersion, palatability, pleasing odor and color, and ease of pourability

Classes of Suspension

  • Depending on application and size:

    • Oral, Topical, Parenteral, based on size (Colloidal, Coarse, Nano), and based on electro-kinetic nature (Flocculated, Deflocculated)

Ingredients of Suspension

  • Key components include:

    • Insoluble drug, vehicles, wetting agents, stability controllers, viscosity modifiers, pH regulators, flavor, colorant, preservatives, sweeteners

Wetting Agents in Suspension

  • Allow for better penetration of the vehicle into the pores of the insoluble particles

Suspending Agents

  • Enhance physical stability and control sedimentation within the suspension

  • Ideal properties involve viscosity adaptability and compatibility

Steps in Preparing Suspensions

  • Include reducing particle size, controlling flocculation, adjusting viscosity, maintaining uniformity, and managing order of mixing

Liquid Dosage Forms Overview

  • Emulsion and Suspension techniques are crucial for formulating effective liquid medicine

Emulsions

  • Two-phased system where one immiscible liquid is finely subdivided and distributed throughout another.

  • Commonly classified by dispersed phase.

Emulsion Production Methods

  • Techniques include:

    • Mortar and pestle trituration

    • Continental/Dry Gum Method

    • English/Wet Gum Method

    • Bottle Method

Ideal Characteristics of Emulsion

  • Should be colorless, odorless, tasteless, non-toxic, and stable at low concentrations.

Emulsifiers

  • Key for stabilizing emulsions; they perform as bridges between phases to enhance stability.

    • Natural, finely divided solids, and synthetic emulsifiers are widely used.

HLB Values

  • The HLB (Hydrophilic-Lipophilic Balance) determines emulsion types; higher values indicate more hydrophilic properties.

Preservatives and Antioxidants in Emulsion

  • Essential to prevent microbial growth and oxidation.

  • Various classes include true antioxidants, reducing agents, and synergists.

Compounding Equipment for Emulsions

  • Includes mechanical stirrers, colloid mills, homogenizers, and systems designed to minimize air ingress.