7 - Solids Theory Flashcards by Karlo Sison

Tablets vs Capsules

in terms of economy/production

Tablets take EXTRA TIME & WORK to develop

almost Never used in early clinical studies

CHEAPER to MASS PRODUCE

Ultimately we want a capsule dosage form that can be EASILY converted to a tablet

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Tablets vs CAPSULES

in terms of market/economy

MORE COSTLY to MASS PRODUCE

almost NEVER favored for marketed products to have HIGH sales volume, unless tablets are TOO difficult to make

Ultimately we want a capsule dosage form that can be EASILY CONVERTED to a tablet

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Hard Shell Capsule

Extemporaneous Compounding

Relatively Easy to formulate & Dispense for low-volume dispensing

Ex. custom dose strengths for INDIVIDUAL patients

Preferred for first-in-man clinical studies due to EASE in:

dispensing / control over distribution

simplicity for dose adjustment

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Basic PhysicoChemical Properties

for designing a Formulation

S + S + SS

Chemical Stability

Temp / pH / oxidation / photochemistry

Solubility

pH / lipophilicity

Solid State Properties of the API

crystal form / salt form (if API is ionizable)

physical stability

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Stability

Tablet & Capsule Dosage Forms

drug must be CHEMICALLY STABLE

Pass through GI tract in solution

survive manufacturing conditions

pH effects

(pH 1-2 / 6-8 / 11-13)

last for several years in solid state

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Soluble

Tablet & Capsule Dosage Forms

drug must be Adequately SOLUBLE

Some solubility in water & lipids

in order to be bioavailable by absorption through GI tract walls

target for a TRANSPORTER SYSTEM

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Solid State

Tablet & Capsule Dosage Forms

Drug must have Desireable SOLID STATE properties

thermodynamically most stable crystalline polymorphic form is desired, adequate solubility

if solubility is INadequate, it can be enhanced, if drug can be produced in a:

metastable crystalline polymorphic form or as the amorphous form

as long as these forms can be PREVENTED from converting to more stable/less-soluble forms

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What is the MOST PREFERRED Solid State form?

thermodynamicaly most stable

Crystalline Polymorphic Form

if this form has adequate solubility!

Amorphous / Metastable crystalline form will suffice if the solubility is inadequate

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Evaluation of Chemical Stability

STABILITY - Tablet & Capsule Formulation

using stress degradation experiments that determine the effect of:

HEAT + HUMIDITY

RXN w/ SOLVENTS (and effect of pH in aqueous solutions)

RXn w/ OXIDIZING AGENTS

Sensitivity to UV & VISIBLE LIGHT

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Thermal Degradation

STABILITY - Tablet & Capsule Formulation

only an acceptable small degradation, when heated to

90*C** in solution for **ONE WEEK

sufficient enough for a liquid product for oral/parenteral use

Also test degradation at:

pH of 1-2 / 6-8 / 11-13

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Thermal Degradation - pH levels

STABILITY - Tablet & Capsule Formulation

ph 1-2 for Stomach Acid

ph 6-8 for Intestinal Fluid

pH 11-13 for Cleaning Media

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Solvolysis

STABILITY - Tablet & Capsule Formulation

Test for Reactions in the Solution, Buffers

Degradation in aqueous media over a range of pH values may permit ID of a

specific pH for MAXIMUM Stability

choice of solid state form for ionizable substances - salt maybe more stable

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Oxidation

STABILITY - Tablet & Capsule Formulation

Reaction with different types of commonly encountered Oxidizing agents like:

Peroxides

Heavy metal ions +/- Oxygen

Radical initiators +/- Oxygen

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Photolysis

STABILITY - Tablet & Capsule Formulation

Rxn when exposed to electromagnetic radiation

UV + Visible Light

UV mimics effect of exposure to ionizing radiation

packaging important

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4 Effects to stress test for SOLUBILITY

STABILITY - Tablet & Capsule Formulation

TSOP

Thermal Degradation

Solvolysis

Oxidation

Photolysis

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Evaluation of Solubility

SOLUBILITY - Tablet & Capsule Formulation

Ionization

Lipophylicity

Intrinsic Dissolution Rate

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Ionization & Stability

SOLUBILITY - Tablet & Capsule Formulation

Many drugs contain chemical moieties (A/B or FxnGroups) that can ionize in AQSolution

Solubility of ionized forms is MANY FOLDS HIGHER in water

pH solubility profile should be generated

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Lipophilicity

SOLUBILITY - Tablet & Capsule Formulation

Optimal obsorption of uncharged drug substances occurs if the drug has about a

100x higher LIPID solubility vs water

but the water solubility must be ENOUGH to dissolve the entire dose in 250-500mL of aqmedia

pH between 1-7

Intrinsic Dissolution Rate

SOLUBILITY - Tablet & Capsule Formulation

Rate at which a compacted disc of this solid dissolved in media = GI Fluids (in stomach/intestines)

Should be measured

Solid State form Selection -

Polymorph Screening

Solid State form Selection - Tablet & Capsule Formulation

Crystalline or Amorphous

Salt or Solvate

Crystal Polymorphism

Solid State form Selection - Tablet & Capsule Formulation

many drugs, esp those with higher MW & limited structural mobility, tend to

Crytallize in MORE THAN 1 polymorphic form

can lose all short-range structure and become amorphous

Physical Properties of Crystal Polymorphs

Solid State form Selection - Tablet & Capsule Formulation

thermodynamically MOST stable Polymorph has:

HIGHEST Melting Point (good)

lowest Solubility (bad)*
slowest Intrinsic Dissolution rate (ugly)*

Solvates & Co-Crystals

Solid State form Selection - Tablet & Capsule Formulation

Some substances crystallize with added solvent molecules trapped in the crystal lattice

Solvation may either STABILIZE or DE-Stabilize reactivity of the solid toward external solvent vapor

Also, other dissolved substances may co-crystillize with the drug to produce a new crystal lattice w/ altered phys properties + altered solid state chemical stability

Amorphous Solids

Solid State form Selection - Tablet & Capsule Formulation

fewer short-range entropy-restricting structural constraints

Physically unstable: spontaneously crystallize

Typically more soluble + faster intrinsic dissolution rate

Typically less chemically stable - more like a drug in solution

Only plus is the solubility / dissolution, no actual formulations that are amorphous YET

**Preformulation Studies** **Issues with S,S,& SS**

May **LIMIT Dosage form choices** May **Dictate constraints on manufacturing processes** may **Impact costs of development** analog w/ better S+S+SS properties may be better drug candidaete, even if it is ***not as potent***

**Identity & Purity** of **API**

**Active Pharmaceutical Ingredient** Imupurities within acceptable limits Drug myst actually be what it **purports to be**

Only a *few* drugs are formulated without adding **some excipients** to make manufacturing possible:

**Filler** **Disintegrants** **Binders** **Lubricants / Anti-Adherants** **Glidants** **Capsule Shell** ***Color / Flavor / Coating***

**Other Excipient Design additions**

**Verify IDENTITY & QUALITY** Prevent CONTERFEITS Moisture content / Impurities

**Excipients** required to make drug products manufacturable are **inert ingredients?** **True or False and why**

**FALSE** Excipients are **NOT** **inert ingredients** They can have **incompatabilities that affect the drug by:** **Stability** **Solubility** **Solid State Properties**

**Excipients -** Test for **Trial formulations or Binary Combinations?**

**_TRIAL FORMULATIONS_** use the best of several candidate trial formulations *In the past we prepared **binary mixtures** THEN examined for S,S,SS properties* **COMBINATIONS** **of exipients** exert **MULTIPLICATIVE** and not just *additive effects* on S,S,SS properties

**Bulk Properties**

All must be determined **BEFORE manufacturing procedure**: **Particle size may also require modification** Particle size **Distribution** Bulk + **Tap Density** **Angle of Repose** **Flow Properties**

**Preferred Dose / Size of solid dosage form**

* Impractical to deliver **LARGE DOSES _\>1gram_*** * Also impractical to deliver **Small Doses _\<10mg_*** without the use of **extensive dilution using fillers** likely to have **mixing/content uniformity problems**

**When is Bioavailability tested for in clinical trials?**

**_PHASE 1_** It is critical to establish that the drug is **actually released** from the **dosage form & absorbed into the body** "**Phase Zero"** initial estimates of **PK & PD** properties

**IVIVC**

Attemp is made to **devise** **dissolution test conditions** _**I**n **V**itro that **C**orrelate with **I**n **V**ivo_ Product **dissolution studies** are conducted to measure **drug release** from the dosage form under **laboratory conditions;**

**What is observed in DISSOLUTION TESTING?**

Tablet must **first disintegrate /** Capsule must **first break open** then **dispersed & dissolved** This process must occur **CONSISTANTLY** with ***minimum variation in performance*** with **multiple samples of he dosage form**

How is **dissolution testing** done?

done using **_Aqueous Media_** **pH 1-2** to mimic _stomach acid_ **pH 5-7** to mimic _intestinal fluid_ Sometimes **surfactants & enzymes** are added to mimic _**bile** surfactants & **pancreatic** enzymes_ **900mL** test volume @ **37\*C + Controlled vessel geometry + controlled stirring rate**

At **what phase** do the studies **indicate that controlling BV may lead to BETTER EFFICACY** when compared to **adverse drug effects?**

**_PHASE 2_** It is normally prudent to develop an **IR dosage form** for **FIRST-IN-HUMAN Studies** **Phase 1** dosage form can be **re-designed & re-engineered** to modify the drug release rate ***(slow it down)*** so it can achieve a **longer duration of action** **and/or** **steadier plasma conc**

**Packaging** in terms of Drug Formulation

Drug must be dispensed in **some sort of container** **Bottles / Vials** = Glass / Plastic + Caps / Cap liner / anti-tampering seal **Blister Packs** = plastic film laminate, foil laminate **Compatibility of the packaging** must be evaluated: **Moisture / Light Barrier?** any **Sorption of drug to components of packaging?**

**Storage** in terms of Drug Formulation

Changes in S,S&SS must be evaluated **throughout the planned shelf life** of the drug under **anticipated storage conditions** Product must **PERFORM** **"Essentially Indetically**" at the end of the shelflife. Equal to how it worked when it was FIRST manufactured

**Quality Assurance** in terms of Drug Formulation Multiple specifications must be met with on-targ results having **minimum variation** **Accuracy & Precision** are both important

* **API** meets all specs * **Dissolution** adequate * **Weight** within correct range * CORRECT **Potency** * **Moisture** content within limits * Acceptable **Appearance** * **Degradation** products within limits * **Mechanical properties** acceptable * Free from **microbial contamination** * Contents sufficiently **uniform** * **Size & Shape** within design specs

**Clinical Development Map**

**API Development Map**

**Dosage form Development MAP**