dosage form design: pharmaceutical and formulation...

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Dosage Form Design: Pharmaceutical and Formulation Considerations

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The Need for dosage forms

To protect the drug substance from the atmospheric oxygen or humidity (coated tablets, sealed ampuls)

To protect the drug substance from gastric acid after oral administration (enteric-coated tablets)

To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavoured syrups)

To provide liquid preparations of drug substances, either as dispersions (suspensions) or as clear preparations (solutions)

To provide rate-controlled drug action(various controlled-release tablets, capsules, and suspensions)

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The Need for dosage forms

To provide optimal drug action from topical administration sites (ointments, creams, transdermal patches, and ophthalmic, ear, and nasal preparations)

To provide for insertion of a drug into one of the body’s orifices (rectal or vaginal suppositories)

To provide for placement of drugs directly in the bloodstream or body tissues (injections) To provide for optimal drug action through inhalation therapy (inhalants and inhalation aerosols)

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General Considerations in dosage form design

systemic use …..oral administration

emergency …..injectable form

nausea, and vomiting…..skin patches, suppositories, injections. infants and children younger than 5 years of age…..solutions, syrups, or suspensions

childhood and even adulthood…..flavored chewable tablet, capsules

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Pre-formulation studies

Physical Description 1- solid: stability, small, accurately dosed, tasteless,70% of the time by community pharmacists

2- liquidProblems:volatile and must be physically Hard to formulate in tablet Solution:sealed from the atmosphere to prevent evaporation loss nitroglycerin Incapsulate in soft capsules Vitamins A, D, and E

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Microscopic Examination Spherical and oval powders flow more easily than needle-shaped powders and make processing easier.

Heat of Vaporisation The amount of heat absorbed when 1 g of a liquid vaporises is known as the heat of vaporisation of that liquid and is measured in calories. aerosol dosage.

The smaller the particle size, the greater the vapour pressure. This demonstrates the importance of personnel protection.

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Melting Point Depression determine the purity of a drug substance, the compatibility of various substances before inclusion in the same dosage form.

The temperature at which the pure liquid and solid exist in equilibrium.

eutectic point

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Particle Size Affect dissolution rate, bioavailability, content uniformity, taste, texture, colour, and stability, flow characteristics, sedimentation rates, absorption.

Polymorphism crystal or amorphous form of the drug substance. Polymorphic forms usually exhibit different physicochemical properties, including melting point and solubility. At least one third of all organic compounds exhibit polymorphism.

The energy required for a molecule of drug to escape from a crystal is much greater than is required to escape from an amorphous powder. Therefore, the amorphous form of a compound is always more soluble than a corresponding crystal form.

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Solubility For a drug to enter the systemic circulation and exert a therapeutic effect, it must first be in solution.


solubility test: an excess of the drug is placed in a solvent and shaken at a constant temperature over a long period until equilibrium is obtained, then the drug will be analysis.

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Solubility and Particle Size small increases in solubility can be accomplished by particle size reduction Solubility and pH Weak acidic or basic drugs may require extremes in pH that are outside accepted physiologic limits or that may cause stability problems with formulation ingredients.

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Dissolution Sedimentation in gastric fluid, it will do so in the form of fine particles with a large surface area. dissolution rate: the time it takes for the drug to dissolve in the fluids at the absorption site, is the rate limiting step in absorption.

The value is expressed as milligrams dissolved per minute per square centimetre.

Ficks first law

Noyes and Whitney law

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Membrane Permeability passage of drug molecules across biologic membranes

The biologic membrane acts as a lipid barrier to most drugs and permits the absorption of lipid- soluble substances by passive diffusion

Data obtained from the basic physicochemical studies, pKa, solubility, and dissolution rate, provide an indication of absorption.

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Partition coefficient The oil–water partition coefficient is a measure of a molecule’s lipophilic character

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Hydrates and Solvates

Hygroscopic powders are those that will tend to absorb moisture from the air.

Deliquescent powders are those that will absorb moisture from the air and even liquefy.

Efflorescent powders are those that may give up their water of crystallisation and may even become pasty.

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Organic Salt considerations

Because many drugs are either weak acids or weak bases and have limited water solubility, they are often used as their “salts” to increase their aqueous solubility.

The dose depends on salt or base form.

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Potency-Designated active Pharmaceutical ingredients

APIs have potencies based on “activity” or “micrograms per milligram” or other standard terms.

These are described for each API in the USP.

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Complex Organic Molecules

Pharmacists involved in working with or handling biologically active proteins must be interested in their stabilisation, formulation, and delivery to the site of action.

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Drug and Drug Product Stability

Stability studies conducted in the pre formulation phase include solid-state stability of the drug alone, solution-phase stability, and stability in the presence of expected excipients.

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Drug Stability: Mechanisms of Degradation

Hydrolysis is a (drug) molecules interact with water molecules to yield breakdown products. For example, aspirin.

Hydrolysis is the most important single cause of drug decomposition. It affects esters or contain such other groupings as substituted amides, lactones, and lactams.

Oxidation destroys aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils. Oxidation is loss of hydrogen and involves free chemical radicals, which are molecules or atoms containing one or more unpaired electrons.

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Drug and Drug Product Stability: Kinetics and Shelf life

Chemical Physical Microbiologic Therapeutic Toxicologic

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Rate Reactions

Zero-Order Rate Reactions

First-Order Rate Reactions

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Pre-formulation studies Enhancing Stability of Drug Products Buffers an aqueous solution, that can resist changes in pH upon addition of an acid or a base. Buffers are composed of a weak acid and its conjugate base or a weak base and its conjugate acid.

Antioxidants sulphites, light, chelating agents, opaque containers.

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Group Activities

individual activities

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Thalidomide

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• Thalidomide was discovered by scientists at a German pharmaceutical company around 1953

• The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative

• Thalidomide was first marketed in 1957 in West Germany

• Thalidomide was primarily prescribed as a sedative or hypnotic

• Thalidomide also claimed to cure anxiety and insomnia

Thalidomide

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• Thalidomide was also effective against nausea and to alleviate morning sickness in pregnant women.

• Thalidomide became an over-the-counter drug in West Germany on October 1, 1957. Shortly after the drug was sold in West Germany, between 5,000 and 7,000 infants were born with malformation of the limbs.

• Only 40% of these children survived

• The negative effects of thalidomide led to the development of more structured drug regulations and control over drug use and development

Thalidomide

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• Thalidomide exists in two mirror-image forms: it is a racemic mixture of (R)- and (S)-enantiomers

• The (R)-enantiomer has sedative effects

• The (S)-isomer causes malformation of the limbs (teratogenic)

• Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.

Thalidomide

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Botulinum

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https://bit.ly/2Hy1xee

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https://bit.ly/2Hy1xee

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MOCK TEST

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Amal

QUESTION 1The initial human dose is usually ..…… of the highest non-toxic dose in animalsالجرعة ا-ولية ا<عطاة ل9نسان يجب أن تكون ……. -على جرعة غير سمية في

حيوانات التجارب

A. 10x (عشرة أضعاف)

B. 1/10

C. 1/100

D. 1/1000

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QUESTION 2In phase 1 clinical trials, the human subjects are usually ……

في الطور ا-ول من اختبارات ا-دوية سريرياً، ا-شخاص اللذين يخضعون

للتجربة هم ……

A. Males volunteers (متطوعون ذكور)

B. Sick children (أطفال مرضى)

C. Maternal parents (الحوامل)

D. Healthy volunteers (متطوعون أصحاء)

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QUESTION 3What is the maximum effective concentration in the figure below?

ما هو الحد ا-على للجرعة العbجية في الشكل أدناه

A. 4.0 mcg/ml

B. 2.0 mcg/ml

C. 4.0 hours

D. 8.0 hours

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QUESTION 4The Lethal doe (LD50) of Botulinum is estimated to be ……… of body weight

الجرعة ا<ميتة الوسطية تقدر ب حوالي ….. من وزن الجسم

A. 2.0 ng/kg

B. 20 ng/kg

C. 5.0 ng/kg

D. 50 ng/kg

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QUESTION 5A medicine is different than a drug because the medicine ..…

الدواء يختلف عن العقار -ن الدواء …..

A. is designed to give positive or negative effects مصمم jعطاء تأثيرات إيجابية أو سلبية

B. Is designed to give positive effect onlyمصمم jعطاء تأثيرات إيجابية فقط

C. contains only the active ingredient يحتوي على ا<ادة الدوائية الفعالة فقط

D. Does not have side effects r يترافق مع أعراض جانبية

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In vomiting, the used dosage forms are:اrشكال الصيدrنية ا<ستخدمة في حاrت اrقياء

A. Skin patches (اللصاقات الجلدية)

B. Suppositories (التحاميل)

C. Inhalation (ستنشاقيةrشكال اrا)

D. A+C

QUESTION 6

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Purity of API can be tested by:تفحص نقاوة ا-واد الدوائية عبر:

A. Microscope (الفحص ا<جهري)

B. Melting point (نصهارrفحص ا)

C. Solubility test (ليةbنحrفحص ا)

D. B+C

QUESTION 7

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Particle size affects: يؤثر حجم ا;جزاء على:

A. Dissolution rate (معدل الذوبان)

B. Flow characteristics (خواص التدفق)

C. Absorption (متصاصrا)

D. All are correct (كل ما سبق)

QUESTION 8

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Weak acidic drugs are soluble in:الحموض الضعيفة منحلة في:

A. pH=7

B. pH less than 7

C. pH more than 7

D. Oils (الزيوت)

QUESTION 9

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During the formulation of proteins, pharmacist must be interested in اثناء صياغة البروتينات فإن الصيد;ني يجب ان يهتم ب:

A. Stabilisation (الثباتية)

B. Melting point (نصهارrنقطة ا)

C. delivery to the site of action (يصال <وقع التأثيرrا)

D. A+C

QUESTION 10

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Pharmaceuticals ILecture 4

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ADMEThe absorption, distribution, metabolism, and

elimination of a drug from the body are dynamic processes that continue from the time a drug is

taken

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AbsorptionThe absorption, distribution, metabolism, and elimination of a drug from the body are dynamic processes that continue from the time a drug is taken

Blood

Not reversibleGastrointestinal tract

Skin

intramuscular

Not reversible

Not reversible

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Absorption

What about intravenous injections?

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Absorption

Blood

Not reversibleGastrointestinal tract

Skin

intramuscular

Not reversible

Not reversible

Intravenous injectionintravenous injection bypasses the absorption barrier

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Distribution• The transfer of drug from the blood to other body locations (compartments)

is generally a rapid and reversible process

• The drug in the blood exists in equilibrium with the drug in the other compartments

Brain

Lungs

Muscles

Liver

Kidneys

Adipose

BloodReversible

Equilibrium

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Distribution• The body locations to which a drug travels may be viewed as separate

compartments.

• Each compartment contains some fraction of the administered dose of drug

BloodReversible

Equilibrium

Brain

Lungs

Muscles

Liver

Kidneys

Adipose

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Distribution

One compartment model

Blood Body CompartmentsReversible

Equilibrium

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MetabolismDuring metabolism a drug substance may be metabolized into pharmacologically active or inactive metabolites, or both.

The metabolism of a drug to inactive products is an irreversible process that leads to the excretion of the drug from the body, usually via the urine

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Prodrugs

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ProdrugsProdrug is a term used to describe a compound that requires metabolic biotransformation (metabolism) after administration to produce the desired pharmacologically active compound

The conversion of an inactive prodrug to an active compound occurs primarily through enzymatic processes

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Why Prodrugs?1. Solubility

A prodrug may be designed to possess solubility advantages over the active drug, enabling the use of specifically desired dosage forms and routes of administration.

2. Absorption

A drug may be made more water or lipid soluble, as desired, to facilitate absorption via the intended route of administration.

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Why Prodrugs?3. Biostability

If an active drug is prematurely destroyed by biochemical or enzymatic processes, the design of a prodrug may protect the drug during its transport in the body

4. Prolonged Release

Depending on the prodrug’s rate of metabolic conversion, it may provide prolonged drug release and extended therapeutic activity.

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ADME

• Gastrointestinal tract, intramuscular injection and subcutaneous injection are subjected to A D M E

• Intravenous Injection is only subjected to D M E

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Principles of Drug Absorption

Before an administered drug can arrive at its site of action, it must cross a number of barriers.

EXAMPLE

• A drug taken by mouth must• Traverse the gastrointestinal membranes (stomach and intestines)• Gain entrance to the general circulation• Pass to the organ or tissue with which it has affinity• Gain entrance to that tissue• Enter its individual cells

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Principles of Drug AbsorptionThe membranes in the body may be viewed in general as a lipid layer (fat containing).

Drugs are thought to penetrate these biologic membranes in two general ways:

1. Passive diffusion

2. Specialized transport mechanisms

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Passive DiffusionPassive diffusion is the passage of drug molecules through a membrane that does not actively participate in the process.

The absorption process is driven by the concentration gradient across the membrane, with the passage of drug molecules occurring primarily from the side of high concentration

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Passive DiffusionThe rate of diffusion of a drug across the membrane depends on:

1. The concentration gradient 2. The affinity for lipid and rejection of water (Hydrophobic)

Because of the lipid nature of the cell membrane, it is highly permeable to lipid-soluble substances.

The greater its affinity for lipid, the faster will be its rate of penetration into the lipid-rich membrane.

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Passive DiffusionCells are also permeated by water and lipid-insoluble substances, it is thought that the membrane also contains water-filled pores or channels that permit the passage of these types of substances.

As water passes in bulk across a porous membrane, any dissolved solute with small enough molecules to traverse the pores passes in by filtration.

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Passive DiffusionCell membranes are more permeable to the un-ionized forms of drugs than to their ionized forms, mainly because of the greater lipid solubility of the un-ionized forms and the highly charged nature of the cell membrane … higher surface area too

Ionized drugs unionized drugs

Water soluble Lipid soluble

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Specialized transport Mechanisms

This type of transfer is for substances that are too lipid insoluble to dissolve in the lipid layer and too

large to flow or filter through the pores.

EXAMPLE Amino acids and glucose

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Specialized transport MechanismsThis type of transport is thought to involve membrane components that may be enzymes capable of forming a complex with the drug at the surface membrane.

The complex moves across the membrane, where the drug is released, with the carrier returning to the original surface

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Specialized transport MechanismsFeatures of specialized transport include:

1. Specialized transport may become saturated as the amount of carrier for a given substance becomes completely bound with that substance resulting in a delay in transport

2. Specialized transport include the specificity for a particular type of chemical structure, so that if two substances are transported by the same carrier, one will competitively inhibit the transport of the other

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Specialized transport MechanismsThere are two types of specialized transport mechanism:

1. FACILITATED DIFFUSION A process where the solute or drug is moved across the membrane with a concentration gradient (it achieves the same concentration inside the cell as on the outside = equilibrium)

2. ACTIVE TRANSPORT A process where the solute or drug is moved across the membrane against a concentration gradient (from a solution of lower concentration to one of a higher concentration = no equilibrium)

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Concentration vs time curve

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Concentration vs time curveFollowing oral administration of a medication, if blood samples are drawn from the patient at specific time intervals and analyzed for drug content, the resulting data may be plotted on graph paper to yield the type of drug blood level curve presented below.

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Concentration vs time curveThe y-axis: The vertical axis represents the concentration of drug in the blood (or serum or plasma)

The x-axis: The horizontal axis (x-axis) represents the time the samples were obtained following the administration of the drug

(Cmax) The peak height concentration

(Tmax) The time of the peak concentration

(AUC) The area under the blood concentration vs time curve

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The Area Under The Curve (AUC)

The AUC is considered representative of the total amount of drug absorbed into the circulation following the administration of a single dose of that drug

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The Area Under The Curve (AUC)Equivalent doses of a drug, when fully absorbed, produce the same AUC.

Thus, two curves dissimilar in terms of peak height and time of peak may be similar in terms of AUC and thus in the amount of drug absorbed

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The Area Under The Curve (AUC)

The smaller the AUC, the lesser drug absorbed

OR

The bigger the AUC, the more drug absorbed

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The Area Under The Curve (AUC)If equivalent doses of drug in different formulations produce different AUC values, differences exist in the extent of absorption between the formulations

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Bioavailability

Bioavailability describes the rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action.

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Bioavailability

Bioavailability is used to determine

1. The amount of drug absorbed from a formulation or dosage form

2. The rate at which the drug was absorbed

3. The duration of the drug’s presence in the biologic fluid or tissue

4. The relationship between drug blood levels and clinical efficacy and toxicity

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Formulation A vs B

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Still Alice

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https://bit.ly/2DDuyUJ

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dosage form design: pharmaceutical and formulation...

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