Curriculum
Lesson 3: Pharmaceutical Technology and Modern Pharmaceutics
📋 Learning Objectives
By the end of this chapter, you will be able to:
- ✓ Understand the principles of preformulation studies and their importance in drug development
- ✓ Identify critical physical and chemical characteristics of drug substances
- ✓ Analyze formulation aspects of solid dosage forms, especially tablets and capsules
- ✓ Evaluate manufacturing processes and quality control tests for pharmaceutical dosage forms
- ✓ Apply principles of controlled drug delivery systems in modern pharmaceutics
🔍 Preformulation
Preformulation is a link between drug discovery and drug development. It is the fundamental step in the rational development of dosage forms. It can also be defined as an investigation of physical and chemical properties of drug substance alone and when combined with excipients.
Goal of Preformulation
- To formulate an elegant, safe, efficacious dosage form with good bioavailability.
- To formulate new dosage form of an already existing drug.
- Determination of all the properties of drug and the best suitable dosage form for the drug molecule.
Physical Characteristics
A. Bulk Characteristics
- Particle Size and Surface Area
- Crystallinity
- Flow properties and Bulk density
- Drug-Excipient Compactibility
- Osmolarity
- Wettability
- Polymorphism
- Hygroscopicity
- Compressibility
- Electrostatic charge
- Rheology
B. Solubility Analysis
- Aqueous Solubility
- Intrinsic Solubility
- Dissociation Constant
- Solubilization
- Partition Coefficient
- Thermal effect
- Common ion effect
- Dissolution
C. Stability Analysis
- Solid State Stability
- Solution state stability
Chemical Characteristics
- Oxidation
- Hydrolysis
- Photolysis
- Racemization
- Polymerization
- Isomerization
- Decarboxylation
- Enzyme decomposition
Polymorphism
Polymorphism is the ability of any compound or element to crystallize as one or more distinct crystal species with different internal lattice.
The effect of polymorphism on bioavailability is the most important consequence for drug substances if the bioavailability is mediated via dissolution. The oldest known example is chloramphenicol palmitate.
Types of Polymorphism
Phase transition: The process of transformation of one polymorph into another, which may also occur on storage or during processing, is called phase transition.
- Enantiotrophic Polymorphs: Phase transition is reversible that means metastable ⇄ stable. E.g., sulphur
- Monotrophic Polymorphs: Phase transition occurs only in one direction metastable→stable. E.g., glyceryl stearate.
Solvates (Pseudopolymorphism)
Solvates are molecular complexes that have incorporated the crystallizing solvent molecule in their specific lattice position and in fixed stoichiometry. When the solvent incorporated in the solvate is water, it is called a hydrate.
A classical method for distinguishing solvates from polymorphs involves observation of the melting behavior of crystals embedded in silicon oil, where upon heating, bubbles of solvent are generated by solvates. In case of polymorphs, no such generation occurs.
Methods to Identify Polymorphism
- Optical crystallography
- Hot stage microscopy: Using this technique, fluid phase transformation as a function of temperature is observed. Generally, silicon oil hot stage microscopy is used for detection of pseudo polymorphs.
- X-ray diffraction method: Using Bragg’s equation: N λ = 2dsin θ (Where d = distance for different planes of crystal, λ = wavelength of x-ray used, θ = angle of incoming beam, n = order of spectrum)
- NMR technique: In this technique, powder sample must be rotated at a special angle with respect to magnetic field.
- FTIR technique: It has been used to quantify binary mixtures of polymorphs.
- Dilatometry: Measure change in volume caused by thermal or chemical effect.
- Microcalorimetry: Used to characterize thermodynamic properties of different molecules.
- Thermal methods: (a) DSC [Differential scanning calorimetry] (b) DTA [Differential thermal analysis] (c) TGA [thermal gravimetric analysis]
- Melting point determination
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Concept Check
Questions:
- What is the primary goal of preformulation studies?
- How does polymorphism affect drug bioavailability?
- What is the difference between enantiotrophic and monotrophic polymorphs?
Show Answers
Answers:
- The primary goal of preformulation studies is to formulate an elegant, safe, efficacious dosage form with good bioavailability by investigating the physical and chemical properties of the drug substance both alone and when combined with excipients.
- Polymorphism affects drug bioavailability primarily through its impact on dissolution rate. Different polymorphic forms have different internal crystal structures, leading to differences in solubility and dissolution rates, which can significantly affect bioavailability, especially for drugs with poor water solubility. For example, the B form of chloramphenicol palmitate is more soluble and has greater bioavailability than form A.
- Enantiotrophic polymorphs can undergo reversible phase transitions between the metastable and stable forms (e.g., sulphur), while monotrophic polymorphs undergo phase transition only in one direction, from metastable to stable form (e.g., glyceryl stearate).
💡 Crystal and Amorphous States
Crystal
A crystal is a solid in which the constituent atoms, molecules, or ions are packed in a regularly ordered, repeating pattern extending in all three spatial dimensions.
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Amorphous Compound
Amorphous forms are usually of higher thermodynamic energy than corresponding crystalline forms, so solubilities as well as dissolution rates are generally greater but due to high energy, they are unstable and tend to revert back to a stable form. This is particularly true for formulations like aqueous suspensions.
In case of amorphous novobiocin suspension, it slowly converts to a crystalline form and thus becomes less and less absorbable and finally loses therapeutic effect. Thus a search for additives was begun to prevent such condition.
Characterization of Amorphous Solids
The only positive way to differentiate amorphous from crystalline solids is by means of X-ray powder diffraction. This technique gives very diffuse reflections of amorphous compounds, where the d distances, the distance between parallel planes in which the atoms of the crystal line cannot be determined as is done with crystalline solids.
Clathrates
A clathrate is a single-phased solid with two distinct components: the host and the guest. The guest is retained in the closed cavities provided by the crystalline structure of the host. Thus it is a non-stoichiometric molecular adduct. The major classes of clathrates are hydroquinone clathrates, water clathrates, phenol clathrates etc.
Pharmaceutical Applications of Clathrates
- Purification: Benzene was purified of one of its usual contaminants thiophene by clathrate formation. Although both form clathrates with monoamine nickel cyanide, benzene is more firmly held in cage structure, so it is preferentially clathrated and separated from solution by filtration.
- Separation of rare gases: Argon is separated from neon by adjusting the pressure conditions in which hydroquinone-argon clathrate is formed, while neon does not form clathrate.
- Separation of optical isomers: Inclusion complexing substance that will separate optical isomers is tri-o-thymotide.
- Storage of inert gases: They are used for convenient storage of inert gases like hydroquinone or to introduce such gases into fairly inaccessible locations. The gas can be released by heating or dissolving the clathrates.
- Mode of action of anesthetics: Non-hydrogen bonding anesthetics work primarily due to clathrate formation of molecules of anesthetic agent with water contained in the neurons and around the neural network.
Comparison of Crystalline and Amorphous Forms
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Concept Check
Questions:
- How do amorphous and crystalline forms differ in terms of solubility and stability?
- What technique is used to differentiate amorphous from crystalline solids?
- What is a clathrate and what are its pharmaceutical applications?
Show Answers
Answers:
- Amorphous forms have higher thermodynamic energy than crystalline forms, resulting in greater solubility and dissolution rates. However, this higher energy state makes amorphous forms less stable, causing them to tend to revert back to more stable crystalline forms over time. This is particularly problematic in formulations like aqueous suspensions.
- X-ray powder diffraction is the definitive technique used to differentiate amorphous from crystalline solids. Amorphous compounds give very diffuse reflections in X-ray diffraction patterns, while crystalline solids show distinct patterns with measurable d-distances (distances between parallel planes of atoms).
- A clathrate is a single-phased solid with two distinct components: the host and the guest, where the guest is retained in closed cavities provided by the crystalline structure of the host. Pharmaceutical applications include purification (e.g., removing thiophene from benzene), separation of gases (e.g., argon from neon) and optical isomers, storage of inert gases, and potentially explaining the mode of action of certain non-hydrogen bonding anesthetics.
📚 Solubility Analysis
Aqueous Solubility
- A drug must possess aqueous solubility for therapeutic efficacy in physiological pH range of 1 to 8 at 37ºC.
- Poor solubility (<10mg/ml) may result into bioabsorption problems.
- If solubility of drug is less than 1 mg/ml, it indicates the need for a salt, particularly if the drug will be formulated as a tablet or capsule.
- In the range 1–10 mg/ml, serious consideration should be given to salt formation.
There are two fundamental properties mandatory for a new compound:
A. Intrinsic Solubility (Co)
The solubility of weakly acidic and weakly basic drug as a function of pH can be predicted with the help of equations:
S=So{1 + (K1/[H+])} ————– for weak acids.
S=So {1 + ([H+]/K2)} ————– for weak bases.
Where, S = Solubility at given pH
So = Intrinsic solubility of the neutral form.
K1 = Dissociation constant of weak acid.
K2 = Dissociation constant of weak base.
The intrinsic solubility should ideally be measured at 2 temperatures:
- (a) 4ºC → to ensure physical and chemical stability.
- (b) 37ºC → to support biopharmaceutical evaluation.
B. Ionization Constant (pKa)
The unionized forms are more lipids soluble and more rapidly absorbed from G.I.T.
The relative concentration of unionized and ionized form of weakly acidic or basic drug in a solution at a given pH can be calculated using the Henderson-Hasselbalch equation.
pH = pKa + log [unionized form]/[ionized form] —for weak bases.
pH = pKa + log [ionized form]/[unionized form] —for weak acids.
Note: 75% of all drugs are weak bases, 25% are weak acids and only 5% are non-ionic Amphoteric.
Methods to Determine Solubility
- Equilibrium solubility method:
- An excess of drug is placed in solvent and shaken at constant temperature over a prolonged time (24–72 h.) till equilibrium is attained.
- Filtration is done.
- Analyze the supernatant via HPLC to determine degree of solubility.
- Turbidometric solubility method.
- Nephlometric solubility method.
- Ultra-filtration LC/MS solubility method.
- Direct solubility method.
Methods to Determine pKa
- Potentiometric method.
- Conductivity method.
- Dissolution rate method.
- Liquid–Liquid partition method.
- Spectrophotometric method.
Solubilization
Many different approaches have been developed to improve drug solubility:
- Micronization
E.g., Griseofulvin shows increased solubility by reducing particle size. - Change in pH
E.g., Solubility of nimesulide increases as pH is increased.
E.g., Etoposide formulation is difficult because of its poor solubility and labile chemical stability so its most stable formulation is Etoposide loaded emulsion (ELE) at pH 4–5. - Cosolvency
Addition of a water miscible solvent can often improve the solubility of a weak electrolyte or non-polar compound in water by altering the polarity of the solvent.
The choice of suitable cosolvent is limited for pharmaceutical use because of possible toxicity and irritancy.
Ideally, suitable blends should possess values of dielectric constant between 25–80.
Commonly used cosolvents are ethanol, sorbitol, glycerin, propylene glycol, dimethylacetamide (DMA), DMSO, etc. - Solubilization by surfactant
E.g., Gelucire 44/14 is a surface active excipient that can solubilize poorly soluble drugs.
E.g., Anionic and cationic surfactants exhibited dramatically higher solubilization for gliclazide, while nonionic surfactants showed significantly lower solubilizing ability. - Complexation
E.g., The complexation of iodine with 10-15% polyvinylpyrrolidone (PVP) can improve aqueous solubility of active agent. - Formation of inclusion compound
E.g., The aqueous solubility and chemical stability of Quercetin can be improved via Complexation with β-cyclodextrin.
E.g., The enhancement of solubilization increased 300 fold for Nimodipine at a polymer concentration 10% by use of water soluble dendrimer based on polyglycerol. - Chemical modification
Many poorly soluble drugs are modified into salt form (water soluble). - Use of metastable polymorphs
E.g., B form of Chloramphenicol palmitate is more water soluble than A and C forms.
Partition Coefficient
A measurement of drug lipophilicity and indication of its ability to cross cell membranes is oil/water partition coefficient in systems such as octanol/water and chloroform/water.
It is defined as ratio of un-ionized drug distributed between the organic and aqueous phases at equilibrium.
Po/w = (Coil/Cwater)equilibrium
- When a solute is added to two immiscible liquids it will distribute itself between the two phases in a fixed ratio, which is referred to as partition or distribution coefficient.
- It is independent of concentration of dilute solution of given solute species.
- Various organic solvents used in determination of partition coefficient include chloroform, ether, amyl acetate, etc.
- Solubility parameter of n-octanol (δ = 10.24) lies midway in the range for major drugs (δ = 8–12). Thus in formulation development the n-octanol-water partition coefficient is commonly used.
- P= (Conc. of drug in octanol)/(Conc. of drug in water)—For unionizable drugs.
- P= (Conc. of drug in octanol)/((1-α)*(Conc. of drug in water))—For ionizable drugs.
- Where α = degree of ionization.
- P > 1 → Lipophilic drug.
- P < 1 → Hydrophilic drug.
- The value of P at which maximum activity of controlled release dosage forms is observed is approximately 1000:1 in octanol/water.
Methods to determine P: (a) Shake Flask Method, (b) Chromatographic Method (TLC, HPLC), (c) Counter Current and Filter Probe method.
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Concept Check
Questions:
- What is the significance of intrinsic solubility in drug development?
- Why is the partition coefficient an important parameter in preformulation studies?
- Name three approaches to improve the solubility of poorly soluble drugs.
Show Answers
Answers:
- Intrinsic solubility (Co) is the solubility of the neutral form of a drug and is a fundamental property that helps predict the drug’s solubility at different pH values. It is significant because it helps determine if salt formation is necessary (when solubility is less than 1 mg/ml), aids in formulation decisions, and supports evaluation of both stability (measured at 4°C) and biopharmaceutical properties (measured at 37°C).
- The partition coefficient is important because it measures a drug’s lipophilicity and indicates its ability to cross cell membranes. It helps predict a drug’s absorption, distribution, and biological activity. Drugs with P > 1 are lipophilic and can more easily cross cell membranes, while those with P < 1 are hydrophilic. The optimal partition coefficient for controlled release dosage forms is approximately 1000:1 in octanol/water, indicating a balance between lipid solubility for membrane permeation and water solubility for dissolution.
- Three approaches to improve solubility of poorly soluble drugs include: (1) Micronization – reducing particle size to increase surface area, as with Griseofulvin; (2) Cosolvency – adding water-miscible solvents like ethanol, sorbitol, or propylene glycol to alter solvent polarity; and (3) Complexation – forming complexes with agents like cyclodextrins or PVP to enhance solubility, as with quercetin-β-cyclodextrin complexes. Other approaches include pH adjustment, surfactant use, salt formation, and using metastable polymorphs.
👩⚕️ Tablets
Types of Tablets
According to drug release rate from the tablet (USP classification):
A. Immediate-Release Tablet
The tablet is intended to be released rapidly after administration, or the tablet is dissolved and administered as solution. It is the most common type and includes:
- Disintegrating tablet (conventional or plain tablet)
- Chewable tablets
- Effervescent tablets
- Sublingual and Buccal tablets
- Lozenges
B. Modified-Release Tablet
They have release features based on time, course or location. They must be swallowed intact.
Disintegrating Tablet (Conventional or Plain Tablet)
Disintegrating tablet is the most common type of tablet that is intended to be swallowed and to release the drug in a relatively short time thereafter, by disintegration and dissolution (fast and complete drug release in vivo).
It includes normally the following type of excipients: filler (with low dose drug), disintegrant, binder, glidant, lubricant and anti-adherent.
Chewable Tablets
Chewable tablets are to be chewed and thus mechanically disintegrated in the mouth, so that no disintegrant is included in its composition. Flavoring, sweetening and coloring agents are important.
Sorbitol and mannitol are common examples of fillers in chewable tablets, (mannitol has negative heat of solution which results in cooling effect and also has sweetening action as previously mentioned under mannitol as a filler).
Advantages of Chewable Tablets
- Provide quick and complete disintegration of the tablet and thus obtain a rapid drug effect after swallowing and dissolution.
- Easy administration, especially for infants and elderly people.
- Could be administered when water is not available.
Examples for chewable tablets are: Chewable Aspirin tablets, Chewable Antacid tablets
Effervescent Tablets
Effervescent tablets are dropped into a glass of water before administration during which CO2 is liberated. This facilitates tablet disintegration and drug dissolution; the tablet disintegration should be complete within few minutes. (Effervescence is a special mechanism for disintegration).
CO2 is created by the reaction between carbonate or bicarbonate and a weak acid such as citric acid or tartaric acid.
Advantages of Effervescent Tablets
- To obtain rapid drug action, for example, analgesics and antacids. Effervescent Paracetamol tablet (analgesic) and effervescent antacid tablets
- To facilitate drug intake, for example, Vitamin C effervescent tablets
Sublingual and Buccal Tablets
They are used for drug release in mouth followed by systemic uptake of the drug. A rapid systemic drug effect can thus be obtained without first-path liver metabolism, because the drug diffuses into the blood, directly through tissues under the tongue in case of sublingual tablets and through oral mucosa in case of buccal tablets. Sublingual tablets are placed under the tongue.
Examples
- Nitroglycerin sublingual tablet; it exerts its action within two minutes for rapid relief of “Angina pectoris” attack, because the sublingual area is rich in blood supply. Nitroglycerine suffers from first-pass metabolism if taken orally.
- Vitamin B12 Sublingual tablet
Lozenges
They are tablets that dissolve slowly in the mouth and so release the drug dissolved in the saliva.
Lozenges may be used for local medications in the mouth or throat, e.g., local anesthetics, antiseptics and antibiotics and systemic drug uptake.
Compressed lozenges are made by using tablet machines with large and flat punches, high pressure is applied to produce hard tablets, so that they dissolve slowly in the mouth.
No disintegrant is included in compressed lozenges composition. Other additives (binder and filler) must have pleasant taste or feeling during dissolution. Common binder used in compressed lozenges is gelatin; common fillers are (Sorbitol, mannitol and glucose). Bradoral® Compressed lozenges, for the treatment of sore throat.
Formulation of Tablets
Types of Excipients
Lubricants
Lubricants are the agents that act by reducing friction by interposing an intermediate layer between the tablet constituents and the die wall during compression and ejection.
Solid lubricants, act by boundary mechanism, results from the adherence of the polar portions of molecules with long carbon chains to the metal surfaces to the die wall. Magnesium stearate is an example of boundary lubricant.
Other is hydrodynamic mechanism i.e., fluid lubrication where two moving surfaces are separated by a finite and continuous layer of fluid lubricant. Since adherence of solid lubricants to the die wall is more than that of fluid lubricants, solid lubricants are more effective and more frequently used.
Antiadherents
Anti adherents prevent sticking to punches and die walls.
Talc, magnesium stearate and corn starch have excellent anti adherent properties. Vegan had suggested that silicon oil can be used as anti adherent.
Glidants
Glidants are added to the formulation to improve the flow properties of the material which is to be fed into the die cavity and aid in particle rearrangement within the die during the early stages of compression.
Starch is a popular glidant because it has additional value of disintegrant. Concentration of starch is common up to 10%.
Talc is a glidant which is superior to starch; its concentration should be limited because it has retardant effect on dissolution-disintegration profile.
Binders
Binders or adhesives are the substances that promote cohesiveness. It is utilized for converting powder into granules through a process known as granulation.
Flow property/fluidity is required to produce tablets of a consistent weight and uniform strength. Compressibility is required to form a stable, intact compact mass when pressure is applied.
These two objectives are obtained by adding binder to tablet formulation and then proceeding for granulation process.
Problems in Tablet Manufacturing
Capping
‘Capping’ is the term used, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap, during ejection from the tablet press, or during subsequent handling.
Reason: Capping is usually due to the air–entrapment in a compact during compression, and subsequent expansion of tablet on ejection of a tablet from a die.
Lamination/Laminating
‘Lamination’ is the separation of a tablet into two or more distinct horizontal layers.
Reason: Air–entrapment during compression and subsequent release on ejection.
The condition is exaggerated by higher speed of turret.
Chipping
‘Chipping’ is defined as the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations.
Reason: Incorrect machine settings, specially mis-set ejection take-off.
Cracking
Small, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’.
Reason: It is observed as a result of rapid expansion of tablets, especially when deep concave punches are used.
Sticking/Filming
‘Sticking’ refers to the tablet material adhering to the die wall.
Filming is a slow form of sticking and is largely due to excess moisture in the granulation.
Reason: Improperly dried or improperly lubricated granules.
Picking
‘Picking’ is the term used when a small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face.
The problem is more prevalent on the upper punch faces than on the lower ones. The problem worsens, if tablets are repeatedly manufactured in this station of tooling because of the more and more material getting added to the already stuck material on the punch face.
Reason: Picking is of particular concern when punch tips have engraving or embossing letters, as well as the granular material is improperly dried.
Binding
‘Binding’ in the die, is the term used when the tablets adhere, seize or tear in the die. A film is formed in the die and ejection of tablet is hindered. With excessive binding, the tablet sides are cracked and it may crumble apart.
Reason: Binding is usually due to excessive amount of moisture in granules, lack of lubrication and/or use of worn dies.
Mottling
‘Mottling’ is the term used to describe an unequal distribution of colour on a tablet, with light or dark spots standing out in an otherwise uniform surface.
Reason: One cause of mottling may be a coloured drug, whose colour differs from the colour of excipients used for granulation of a tablet.
Double Impression
‘Double Impression’ involves only those punches, which have a monogram or other engraving on them.
Reason: At the moment of compression, the tablet receives the imprint of the punch. Now, on some machines, the lower punch freely drops and travels uncontrolled for a short distance before riding up the ejection cam to push the tablet out of the die, now during this free travel, the punch rotates and at this point, the punch may make a new impression on the bottom of the tablet, resulting in ‘Double Impression’.
Quality Control Tests for Tablets
Size and Shape
- The thickness of individual tablets may be measured with a micrometer.
- Tablet thickness should be controlled within ±5% variation of a standard value.
Weight Variation
- Twenty tablets are weighed individually and the average weight is calculated. The individual tablet weights are then compared to the average weight.
- Not more than two of the tablets must differ from the average weight by not more than the percentages stated in table.
Content Uniformity
- Applicable to all coated and uncoated tablets and all capsules containing 50 mg or smaller sizes.
- Tablet monographs with a content uniformity requirement do not have weight variation requirements.
- For content uniformity test, representative samples of 30 tablets are selected and 10 are assayed individually. At least 9 must assay within ±15% of the declared potency and none may exceed ±25%.
Hardness or Crushing Strength
- The resistance of tablets to capping, abrasion or breakage under conditions of storage, transportation and handling before usage depends on its hardness.
- The Monsanto or Stokes hardness tester measures the force required to break the tablet when the force generated by a coil spring is applied diametrically to the tablet.
- The Strong-Cobb Pfizer and Schleuniger apparatus which were later introduced, measure the diametrically applied force required to break the tablet.
Friability
- It is usually measured by the use of the Roche friabilator.
- A number of tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus.
- After 4 minutes of this treatment or 100 revolutions, the tablets are weighed and the weight compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage.
- A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked up.
Disintegration
- The disintegration test is a measure of the time required under a given set of conditions for a group of tablets to disintegrate into particles which will pass through a 10 mesh screen.
- The disintegration test is carried out using the disintegration tester which consists of a basket rack holding 6 plastic tubes, open at the top and bottom, the bottom of the tube is covered by a 10-mesh screen.
- For most uncoated tablets, the BP requires that the tablets disintegrate in 15 minutes (although it varies for some uncoated tablets) while for coated tablets, up to 2 hours may be required.
Dissolution
- Dissolution may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition.
- At least 75% of the drug should get dissolved in 45 min.
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Concept Check
Questions:
- What are the differences between immediate-release and modified-release tablets?
- What causes capping and lamination in tablet manufacturing?
- Name three quality control tests for tablets and explain their significance.
Show Answers
Answers:
- Immediate-release tablets are designed to release the drug rapidly after administration, providing quick onset of action. They include conventional disintegrating tablets, chewable tablets, effervescent tablets, sublingual/buccal tablets, and lozenges. Modified-release tablets, on the other hand, have controlled release features based on time, course, or location. They must be swallowed intact to maintain their release characteristics and are designed to optimize treatment when different drug levels are needed at different times.
- Both capping (separation of the upper or lower segment of the tablet) and lamination (separation into distinct horizontal layers) are primarily caused by air entrapment in the tablet during compression and subsequent expansion on ejection from the die. Lamination is exacerbated by higher turret speeds. Other contributing factors include poorly finished dies, deep concave punches, excessive moisture in granules, and rapid decompression during the tableting process.
- Three important quality control tests for tablets include: (1) Weight variation test – measures consistency in tablet weight, with limits on how much individual tablets can deviate from the average weight; (2) Hardness or crushing strength test – measures the force required to break a tablet, indicating its resistance to capping, abrasion, or breakage during handling and storage; (3) Dissolution test – measures the amount of drug released into solution over time, which correlates with bioavailability and is critical for therapeutic efficacy. At least 75% of the drug should dissolve within 45 minutes.
🔄 Capsules
Capsules are mainly of two types:
- Hard Gelatin Capsules
- Soft Gelatin Capsules
Hard Gelatin Capsule (Dry Filled Capsule)
The hard gelatin capsule consists of a base or body and a shorter cap, which fits firmly over the base of the capsule. It is mainly used for Powder, Granules, Pellets.
Physical Specification for HSG
Composition
Gelatin
- Bloom Strength (Gel strength): It is measured in Bloom Gelometer. It indicates strength of cross-linked gelatin molecules. It should be 150 – 250 grams.
- It is determined by measuring the weight required to remove a plastic plunger that is inserted 4 mm into 6.66% gelatin solution at 25°C for 17 hours.
- Viscosity: It indicates molecular chain length. It should be 25 to 45 millipoise.
- Type A gelatin: Derived from acid treated precursor. Isoelectric pH is 9.0 and obtained from pork skin. It imparts elasticity/plasticity and clarity to the shell.
- Type B gelatin: Derived from alkali treated precursor. Isoelectric pH is 4.7, obtained from the bone. It imparts toughness to the shell.
- Acid-Bone gelatin: Isoelectric pH is 5.5 to 6.0.
- Iron Content: Less than 15 ppm. Dark Spot on Shell indicates migration of iron sensitive ingredients from the filled capsule.
- Water or Moisture content: 12–15%
- Colourants and Opacifier: (TiO2 Dyes and Other) Functions: Render the shell opaque, Protection against light, Conceal the content
Solubility Limit for Empty Capsules
Water Resistance
Fails to dissolve in water at 20° to 30°C in 15 min.
Acid Solubility
Should get dissolved in less than 5 min in 0.5% aq. HCl at 36 to 38°C.
Steps of Manufacturing of Hard Gelatin Capsule Shell
- Centrifugal Casting method
- Dip-Pin method (Mostly used on commercial scale)
- Gelatin Solution
- Raw gelatin and water are mixed in the ratio of 1: 2 and processed at precise temperature in Saffroys melting systems.
- After vacuum is applied, the solution is received in jacketed tanks.
- Colours and preservatives are added before taking to the capsule machine.
- Dipping
- Setting/Spinning
- Drying
- Stripping
- Capsule halves are individually stripped from the pins using bronze jaw.
- Cutting
- Caps and body halves are trimmed to narrow tolerance as per standards.
- Joining
- Gelatin Solution
Filling of Capsule
Steps
- Rectification: Empty capsule are oriented so that all point in same direction i.e., body end downward.
- Separation of Body and cap: Vacuum applied body pull down into lower portion of split bushing or split filling rings.
- Dosing of Fill material
- Joining and Ejection: Capsule are joined by peg rings. it forces the capsule body against the closing plate. Filled capsules are ejected via compressed air.
- Collection: Filled capsule are collected through Chute.
Dosing of Fill Material
Direct filling method
- Auger filling method (Free flowing powder filled)
Examples of Machine–Eli–Lilly, Parke–Devis, Perry - Vibration assisted filling
Example of Machine-Osaka
Indirect filling method
- Tamp-Filling Method (Dosing disk)–JKF or Bosch or Hoflinger-Karg
- Dosator Machine–Zanasi, Macofar, MG-2, Farmatic
Soft Gelatin Capsule (Soft gel/Soft Elastic Capsule/Wet Filled Capsule)
One piece hermetically sealed soft gelatin shell containing a liquid, a suspension or semisolid.
Note:
- Accogel machine fills dry powder in soft gelatin capsule.
- Most widely used vehicles are oils e.g., Vegetable oils (Soyabean, castor oil), Mineral oil, SAA (Polysorbate 80), PEG 400 and 600.
- pH of encapsulated preparation should in between 2.5 to 7.5.because more acidic pH causes hydrolysis of gelatin shell. More alkaline pH cause tanning of gelatin shell (Reduce the solubility)
- Formulation of Suspension for SGC involves Base Adsorption consideration.
- Base Adsorption (BA) = weight of Base/Weight of Solid
- BA is number of grams of liquid base required to produce a capsutable mixture with 1 gram of solid.
- Minim per gram (M/G) = (BA + S) × V/w
- Base adsorption is used to determine minim per gram factor of solid.
- M/G is volume in minim that is occupied by one gram of solid(S) plus weight of liquid base requied to produce a capsutable mixture.
- Lower the BA of solid, higher the density of mixture and thus smaller the capsule size.
- Most widely used Suspending agents are-
- For Oily base – Wax mixture
- For Non-Oily base – PEG4000 and 6000
Composition of Soft Gelatin Capsule Shell
- Gelatin
- Plasticizer: glycerin, sorbitol, Propylene Glycol
- Water or Moisture Content: 6 to 10% (Moisture Content is determined by Toluene Distillation Method or Azeotropic Distillation.)
- Preservatives: Methyl and Propyl Paraben (4:1)
- Colourants: Fd and C, Certified Lakes
- Opacifier: Titanium Dioxide (0.2 to 1.2%)
- Flavouring Agent: Ethyl Vanillin (0.1%)
- Fumaric acid is added to aid solubility and to reduce aldehyde tanning of gelatin. While Formalin treatment reduces the solubility of shell.
Hardness of Soft Gelatin Capsule Shell
It is determined by weight ratio of dry plasticizer to dry gelatin.
Important Tests
1. Weight Variation test–20 Capsules
2. Disintegration Test
3. Content Uniformity
Applicable to Potent drugs
4. Content of Active Ingredients
100 ± 10%
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Concept Check
Questions:
- What are the key differences between hard gelatin capsules and soft gelatin capsules?
- What is Bloom strength and why is it important for gelatin used in capsule manufacturing?
- How does the pH of the fill material affect soft gelatin capsules?
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Answers:
- Hard gelatin capsules consist of two parts (body and cap) and are primarily used for filling dry materials like powders, granules, and pellets. They have a moisture content of 12-15%. Soft gelatin capsules, on the other hand, are one-piece hermetically sealed units designed to contain liquids, suspensions, or semi-solids. They have a lower moisture content (6-10%), contain plasticizers for flexibility, and use a different manufacturing process. Soft gelatin capsules also have longer disintegration time (60 min vs. 30 min for hard capsules).
- Bloom strength is a measure of the gel strength of gelatin, indicating the strength of cross-linked gelatin molecules. It’s measured using a Bloom Gelometer and should be 150-250 grams for capsule manufacturing. This property is important because it determines the capsule’s mechanical strength, elasticity, and integrity during production and storage. Inadequate Bloom strength could lead to brittle capsules that break easily or capsules that don’t maintain their shape, while excessive strength might affect disintegration properties.
- The pH of fill material in soft gelatin capsules should be between 2.5 and 7.5. Fill materials with pH outside this range can affect capsule integrity and stability. Highly acidic fill materials (pH < 2.5) can cause hydrolysis of the gelatin shell, weakening it and potentially leading to leakage. Highly alkaline fill materials (pH > 7.5) can cause tanning of the gelatin shell, reducing its solubility and potentially affecting drug release and bioavailability.
🧪 Parenterals
Sterile products are dosage forms of therapeutic agents that are free of living microorganisms. These may be injectable, ophthalmic, or irrigating preparations.
Definition
Parenterals are sterile preparations intended for administration under or through one or more layers of skin or mucous membranes.
Routes of Administration
Formulation Additives for Parenterals
Aqueous Vehicle
- Sodium chloride injection, Ringer solution
- Dextrose solution, Lactated-Ringer solution
- WFI (Ideal for parenteral)
Water Miscible
- Ethyl alcohol, Propylene glycol
- PEG 300, 400, 600, Glycerine
Non-aqueous
- Fixed oils–Ethyl oleate, Isopropyl myristate, Peanut oil, Seasame oil, Corn oil, Cotton seed oil, Soyabean oil
Anti-microbial Preservatives
Evaluation of Parenteral Products
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Concept Check
Questions:
- What is the primary difference in the types of preparations that can be administered via the I.V. route versus the I.M. route?
- What is the purpose of the Leaker test and to which parenteral container is it applicable?
- What are the two main methods for sterility testing of parenteral products?
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Answers:
- The primary difference is that only aqueous preparations (solutions) can be administered via the Intravenous (I.V.) route. The Intramuscular (I.M.) route is more versatile and can accommodate aqueous solutions, oily solutions, and suspensions.
- The Leaker test is a packaging integrity test designed to detect improperly sealed containers. It is applicable only to ampoules. Defective ampoules are identified when a colored dye (e.g., 1% Methylene Blue) enters the ampoule under vacuum.
- The two main methods for sterility testing are: (1) Membrane filtration, where the product is passed through a 0.22-micron filter which is then cultured; and (2) Direct inoculation, where a sample of the product is directly added to sterile culture media.