Lecture 1

Capsules

A solid dose where the drug + excipients are sealed inside a soft or hard shell that dissolves in water.

Solid dosage form wherein drug and excipients are enclosed within a soft or hard soluble shell

Why are capsules good

Patient compliance - easier to swallow and eliminates bad tastes

• Taste masking of API

• Flexible and rapid manufacturing

• Lower cost

• Can be used for combination products

• Unlike tablets, liquids can also be filled

Easier to swallow; hide bad taste (taste masking); fast and flexible to manufacture; cheaper; can hold combination products; unlike tablets, can be filled with liquids.

Versatile Fills in Capsules

• Powders & Granules

• Pellets

• Mini-tablets

• Beads

• Liquids

• Semi-solids

Pellets

• Small coated spheres for controlled/delayed drug release

• Tiny coated spheres inside capsules for controlled/delayed release.

Mini Tablets

• capsules contain mini tablets

Beads

• for extended release applications

• Used in capsules for extended release.

Types of Capsules

Gelatin based (animal source) → Hard gelatin and soft gelatin

HPMC based and pullulan based or vegetarian alternatives

Advanced Capsule Types

• Enteric Capsules

• Controlled Release Capsules

• Liquid filled hard capsules

• Tamper evident capsules

• Multi-part capsules: solid and liquid compartments – different release times

• Pediatric capsules

Hard Capsules

Two interlocking halves (body and a cap)

• Capsule material: Gelatin / hydroxypropyl methyl cellulose

• Contains water (acts as plasticizer for shell)

• Are aqueous soluble - dissolves in water

Hydroxypropyl methylcellulose

Vegetable, Low moisture content (4%), More soluble (as low as 10°C)

Gelatin

Non-toxic, Strong flexible film, Shell has a high moisture content (13-16%) - if too dry will break!

• Insoluble below 30°C

Coni-Snap capsule features

Tapered rim (easy closing), dimples (keep round shape), air vents (let air escape during high-speed filling), locking rings (leak-free closure), rounded ends (stronger).

Capsule Sizes

Fill amount ranges from 65 mg to 1 gram

Capsule 000 = more volume to capsule size 5 = smaller volume (smaller)

Disadvantages of Hard Capsules

Compatibility issues with drugs that are

• Hygroscopic (absorb water)

• Deliquescent (absorb so much water they dissolve)

• Efflorescent (lose water)

• Water soluble

May be tampered with

Soft Gelatin Capsules 1

Single hermetically (airtight) sealed shell

• Filled with drugs dissolved or dispersed in liquids or semisolids

Soft Gelatin Capsules 1 advantages

Better oral bioavailability; protects from light and oxygen; good dose uniformity for potent/cytotoxic drugs; good for drugs with low melting points; faster onset (drug is already dissolved); masks taste.

Example of soft gel

Ibuprofen softgel gets to a higher peak concentration faster than the ibuprofen tablet.

Soft Gelatin Capsule Fills

Suitable Liquids

• Water immiscible compounds, Water miscible compounds, Suspensions, Emulsions, Microemulsions

Unsuitable liquids

• Water (>5%), low molecular weight water soluble compounds (e.g., alcohols, ketones)

Hard Gelatin Capsules

Fill: Dry powder, pellets

Heat sensitivity: Tolerate hot climates

Gelatin content: Less gelatin

Onset: Slower (needs fill to be disintegrated/dissolved)

Bioavailability: Standard

Best For: Thermostable substances

Cost: Lower

Hard capsules can also accommodate certain liquids (these are specialized)

Soft Gelatin Capsules

Fill: Liquid/semi-solid drugs, oils, poory soluble drugs

Heat sensitivity: Sensitive to heat

Gelatin content: 4-5x more gelatin

Onset: Faster (pre-dissolved drug)

Bioavailability: can enhance bioavailability

Best For: Poorly soluble, lipophilic APIs,

Cost: Higher

Preparation of Hard Capsules

Drug powder, pellets, granules, etc are filled into the body and then capped

• The joint may be sealed

• Capsule is then polished and evaluated for quality

• There are capsule filling machines available for low volume compounding purposes (manual) and for large scale manufacturing (automated)

Preparation of Softgels

Gelatin is melted

• Molten gelatin is fed as ribbons through a rotary die

• As the ribbons pass between two rotary dies, drug dispersed or dissolved in a liquid is then injected into space between them

• Ribbons are then sealed and cut to form softgels

Case Study - Neoral vs. Sandimmune

Cyclosporine is highly lipophilic with variable oral absorption. Early formulations (Sandimmune® in hard gelatin capsules/solution) had poor bioavailability (~20–30%) and high variability.

Softgel (Neoral®):

• Newer softgel. Contains a SMEDDS inside. Bioavailability higher and more consistent (~50%) = better immunosuppressive control.

• Self-MicroEmulsifying Drug Delivery System. A lipid mixture that spontaneously forms tiny droplets in GI fluid, so the drug dissolves better.

Softgels can hold lipid-based self-emulsifying systems, which improves bioavailability.

Compounding Capsules

Pharmacists can easily prepare capsules to serve the needs of the individual primary care provider and patient.

• For some patients who cannot swallow a tablet but can swallow a capsule, the pharmacist can convert many tablets into a capsule dosage form.

• Capsules enable the primary care provider and pharmacist to combine several drug products into one dosage form.

• With the agreement of the pharmacist, capsules can be opened to mix with food or drinks.

• Softgel capsules require special processing equipment

• Compounded capsules are typically hard capsules

Selection of Capsule Size

Large size 000 and 00 may be hard to swallow

Small size 4 and 5 may be hard to handle

11, 12, 13 are veterinary use because they are larger

Selection of Capsule Size continued

• Patient Preference: Capsule sizes generally preferred: 0, 1, 2, 3 (easy to swallow and handle)

• Dose of Active Ingredient: The amount of drug required per capsule affects size selection

• Density of Powders: Depends on properties of drug and excipients

• Bulk Density (g/ml) = Weight of powder in cylinder / Volume occupied by powder

• Tap Density (g/ml) = Weight of powder in cylinder / Volume after 200 taps

• % Compressibility (Carr’s Index) = (1 − Bulk Density / Tap Density) × 100 → measures flow/compression ability

• Final Capsule Size Selection: Often determined by trial and error based on all above parameters

Rule of 7

1. Convert weight of powder/capsule into grains (1grain = 0.065 grams

2. subtract the number of grains from 7

3. If resulting number is -3 then 000, -2 = 00, -1 or 0= 0, +1 =1, +2 = 2, +3 = 3, +4 = 4, +5=5

Capsule Quality requirements

• Added Substances: Should be harmless, ensure accurate dosing, and must not interfere with drug bioavailability or assay accuracy

• Containers: Must be tight, well-closed, and light-resistant to protect the capsules

• Moisture Permeation: Test Measures moisture leakage into the container/closure system

• Dissolution Test: Performed same way as for tablets to assess drug release

• Weight Variation / Content Uniformity: Ensures each capsule contains consistent weight and drug content

• Stability Testing: Evaluate under stress (temperature, light, humidity); include drug–excipient and container compatibility studies

• Content Labelling: Label must state the amount of each active ingredient.

Some disadvantages

Possibility of tampering, limited suppliers of capsule shells, unsuitable for high soluble salts, Not suitable for hygroscopic, deliquescent, drugs, not suitable for efflorescent drugs, unsuitable for drug/excipients that solubilize gelatin

Tablets

Tablets – compressed solid dosage form; >50% of drug products.

Advantages:

• Easy to administer, Can be scored for splitting, Low-cost mass production, Acceptable

Disadvantages:

• Hard to swallow for some (e.g., children, elderly)

Tablet Category Classification

Release Rate = Immediate release and modified release

Route of administration = sublingual, buccal, oral, vaginal, rectal

Coating = film coated, sugar coated, and uncoated

Types: Single layer, multi later, tablet within tablet

Types of tablets

immediate release, extended release, delayed-release, film-coated, sugar-coated, enteric-coated, chewable, dispersible, orodispersible

Compressed Tablets

Tablets made by compression of powders or granules

• simplest and common type of tablets

Coated Tablets

Tablets with a protective outer layer applied after compression

• Sugar (taste masking), film (appearance), enteric coating (protects from stomach acids)

Effervescent Tablets

Contains acid base combination and releases CO2 in water

• Rapid disintegration, avoids swallowing

Orally Disintegrating Tablets

Tablets designed to disintegrate or dissolve rapidly on the tongue without water, usually within 30 second

• Good for dysphagic patients, pediatrics, geriatrics

Chewable Tablets

Tablets designed to be chewed and swallowed

• Children, patients with swallowing difficulty

Role of Excipients

Modify powder properties

• Aid in manufacturing processability

• May improve bioavailability

• May improve stability

Characteristics of an Ideal Excipient

- Physiologically inert, Non-toxic, Stable. Low cost, Compatible with other excipients

Category of Excipients

Diluents, Disintegrating agents, Binders, Lubricants, Glidants, Wetting agents/ surfactants; Coloring, flavoring, and sweetening agents

Excipients in Tablets

Lubricant/Glidant: Improves flow and tableting process

Filler-Diluent: increases volume, making tablets manageable

Coating: Protects from moisture, pleasant taste - can control dissolution and more

Disintegrant: Makes tables disintegrate faster

Binder: Glues the different tablet components together

Solubilizer: Improves drug solubility to be effective

Tablet Manufacturing Methods

Single punch/die manual, Automated/large scale tablet press, 3D printed tablets

There is only one 3D printed FDA approved tablet. Do you know what it is?

Spritam - levetiracetam

Tablet Categories – Release

• Immediate Release: Formulated to release the drug rapidly after administration

• Extended Release: Designed to release the drug at a prolonged rate for extended therapeutic action

• Delayed Release: Designed to release the drug with a lag time i.e. not immediately

Immediate Release Dosage Form - FDA Def

Defined using in-vitro dissolution testing.

• Highly soluble drugs (BCS Class I and III): at least 85% dissolves within 15-30 minutes. Poorly soluble drugs: at least 85% dissolves within 60 minutes.

• May include disintegrating agents, especially for orally disintegrating tablets (ODTs).

Steps Involved in Immediate Release

Step 1: Tablet or capsule form

Step 2: Tablet or capsule breaks into granules containing superdisintegrants in aqueous media

Step 3: Granules swell due to the action of superdisintegrants, promoting further breakup and dissolution.

Tablet In Vitro Dissolution Testing

Dissolution testing measures the rate and extent of drug release from a solid dosage form in an in vitro (not in animal or human) setting.

• Provides a link between in vitro testing and in vivo performance.

• Critical for quality control, bioequivalence, and formulation development.

• Supports prediction of bioavailability and establish IVIVC (in vitro in vivo correlation).

• Supports regulatory submissions (ANDA, NDA).

Dissolution Apparatus

Apparatus

• Standardized apparatus called USP apparatus 1, 2, 3,…

• USP Chapter <711> summarizes all apparatuses for dissolution testing of tablets

• Non-standardized apparatus (e.g. beaker) can be used but control of certain parameters stirring speed, temperature, hydrodynamics will be challenging

Dissolution Media

• Aqueous simulated media (simulated gastric fluid (SGF), simulated intestinal fluid (SIF), SGF fasted (SGFF),….)

• pH

• Buffering capacity

• Temperature (typically 37°C)

Apparatus 1

Apparatus 1 (Rotating Basket):

• Tablet placed in a basket that rotates and immersed in dissolution media basket

• Applicable to several dosage forms including tablets, capsules, suppositories

Tablet sits in a rotating basket in the media. Works for tablets, capsules, suppositories.

Apparatus 2 (Paddle):

• Tablets sits at the bottom of the dissolution basket while paddle stirs the media

• Widely used for tablets

Tablet sits at the bottom while a paddle stirs. Most widely used for tablets.

Dissolution Apparatus 3

Apparatus 3 (Reciprocating cylinder):

• Dosage form held in a cylindrical tube with screens and the tube moves up and down (reciprocates) in the media

• Mimics conditions in the GIT with changing mechanical forces

Dose in a tube with screens that moves up and down in the media. Mimics the GI tract with changing mechanical forces.

Apparatus 4 (Flow-through cell):

• A flow-through cell holds the tablet, while dissolution media is pumped through it

• Suited for products requiring flow

• Suited for low soluble drugs

Tablet held in a cell while media is pumped through it. Suited for products that need flow and low-solubility drugs

Quality Control of Tablets

• Hardness & Friability: Measures the tablets' mechanical strength and resistance to chipping, crucial for handling and transport

• Moisture Permeation Test: Measures moisture leakage into the container/closure system

• Disintegration Measures: time taken for tablet to breakdown into small pieces in a medium (e.g. simulated gastric fluid)

• Dissolution Test: Measures rate and extent of drug release from the tablet

• Weight Variation / Content Uniformity: Ensures each tablet contains consistent weight and drug content (specification: within 90-110% of targeted weight and drug content)

• Stability Testing: Evaluate product quality changes over time under various storage conditions (temperature and humidity) as per ICH

• Content Labelling Requirement: Label must declare amount of each active ingredient present

ICH

International Conference on Harmonization