Solid Dosage Forms Flashcards
Reservoir Design and SDF testing
1
Q
Why is transdermal delivery ideal for APIs with short elimination half-lives?
A
Reduces the need for frequent dosing
2
Q
Which skin layer is in contact with the external environment? Which skin layer contains blood vessels and nerve endings? What type of tissue is this layer made of?
A
Epidermis
Dermis
Elastocollagenous stroma
3
Q
Which skin layer is the deepest and made of adipose tissue? What produces the elastocollagenous stroma in the dermis?
A
Subcutis
Fibroblasts
4
Q
How much thicker is the epidermis on the soles of feet compared to eyelids? What are the two layers of the dermis? Which dermal layer contains small blood vessels and more matrix? Which dermal layer forms the bulk of the dermis and contains lymphatics?
A
13x
Papillary and reticular dermis
Papillary
Reticular
5
Q
Where is the main blood supply for the skin located? Is there blood supply in the epidermis? How is blood flow variation within the dermis important?
A
Dermis from subcutaneous vessels
No
Thermoregulatory organ function
6
Q
What is a major limitation of transdermal drug delivery? What skin layer is a rate-limiting barrier in transdermal drug delivery?
A
Poor drug permeability
Stratum corneum
7
Q
What type of barrier is the stratum corneum? What does the stratum corneum protect against? Why is diffusion difficult for polar molecules in the stratum corneum?
A
Lipophilic
Toxins and water loss
Tightly joined epidermal cell membranes
8
Q
What does the stratum corneum’s structure resemble? What are the three routes a molecule can cross the stratum corneum?
A
Bricks with lipid mortar
Intercellular, transcellular, appendageal
9
Q
Why is the appendageal route often insignificant? What are the two layers of the bilaminate membrane the skin can be considered?
A
Low number of appendages
Stratum corneum and viable tissue
10
Q
What kind of layer is the stratum corneum considered? What kind of layer is the viable tissue (dermis & part of epidermis) considered? How does the diffusion of polar drugs compare in viable tissue vs. stratum corneum?
A
Lipophilic
Hydrophilic
Faster in viable tissue
11
Q
If a drug diffuses slowly through the stratum corneum, what controls skin permeability? If a drug diffuses quickly through the stratum corneum, what influences permeability? What happens to transfer from stratum corneum to viable tissue as K increases?
A
Stratum corneum alone
Partition coefficient
Become less favourable and slower
12
Q
When are partitioning of the drug the rate-limiting step?
A
At large K values
13
Q
What are incorporated into formulations to increase transdermal drug administration? Into what two broad categories can chemical ones be divided?
A
Penetration enhancers
Partitioning and diffusion
14
Q
What is the lipid-protein-partitioning theory about?
A
Mechanisms of penetration enhancers
15
Q
According to the lipid-protein-partitioning theory, what 3 potential mechanisms may penetration enhancers act by?
A
- Alter the intercellular lipid structure between the keratinocytes to increase diffusivity
- Modify intracellular protein domains in the stratum corneum
- Increase the partitioning of the drug into the skin tissue
16
Q
What properties should an ideal chemical penetration enhancer possess?
A
- Odourless and colourless
- Specific in mode of action
- Pharmacologically inert
- Compatible with drugs and other excipients
- Chemically and physically stable
- Non-allergenic, non-irritant and non-toxic
- The action should be reversible
- Provide a rapid effect for a predictable duration of time
17
Q
What is polyarginine thought to do? What is magainin?
A
Disrupt or penetrate stratum corneum lipids
A pore-former
18
Q
What do metabolic methods of biochemical enhancement aim to do? What does stripping do in physical enhancement?
A
Inhibit repair and slow barrier recovery
Shorten the API path
19
Q
How does thermal ablation work? What is the rate of drug delivery generally proportional to in iontophoresis?
A
Disrupting and removing stratum corneum layers
Applied current
20
Q
How does electroporation work? What do microneedles penetrate?
A
Lipid rearrangement and pore formation
Epidermis leaving micron-sized pores
21
Q
What is the molecular weight limit for transdermal APIs? How does API concentration affect absorption?
A
<500 Da
Higher conc., higher absorption
22
Q
Which route does hydrophilic APIs use across the stratum corneum? Which route does lipophilic APIs use across the stratum corneum?
A
Intercellular
Transcellular
23
Q
What is the recommended IV dose limit for transdermal drugs?
A
Below 20 mg/day
24
Q
How do penetration enhancers reduce diffusional resistance? How does hydration affect skin permeability?
A
Disorder lipid layer, denature keratin, swell corneum
Higher hydration, greater permeability
25
What happens to the bilayer when water hydrogen bonds with polar head groups?
Becomes more fluid
26
What happens when the skin acts as a reservoir for some APIs? How does API metabolism in the skin affect bioavailability?
Reduces permeation and longer lag times
It affects the bioavailability
27
What are Phase I metabolic processes that occur in the skin? Compared to the liver, how much first-pass metabolism occurs in skin?
Oxidation, reduction, hydrolysis
10%
28
How do male and female skin generally differ?
Males have larger keratinocytes and pores
29
What happens to the epidermis and dermis with aging? What happens to hydrophobic drug permeation with aging? What happens to less lipophilic drug permeation with aging?
They thin
Does not change
Decreases
30
To what is the decreased permeation of less lipophilic drugs in the elderly linked?
Hydration of stratum corneum
31
How does percutaneous absorption vary based on ethnicity? What may lower permeation across Afro-Caribbean skin be linked to?
Variations are observed
Skin structure differences
32
What are some characteristics of Afro-Caribbean skin?
More keratinocyte layers in the stratum corneum
High cellular cohesion between keratinocytes
Higher lipid content
Lower water content in the stratum corneum
33
What can damaged or diseased skin lead to in transdermal drug delivery?
Overabsorption -> ADRs
34
What effect do diseases like eczema have on the stratum corneum?
Reduce barrier nature
35
What are the advantages of transdermal over oral administration?
- Peak and valley levels in the serum are avoided
- First-pass metabolism is avoided and skin metabolism is relatively low
- Less frequent dosing regimens are needed
- Reduced variability between patients
- The easy accessibility of the skin and relatively large surface area for absorption
- Non-invasive technique making it more patient friendly increasing compliance
36
What are the disadvantages of transdermal drug delivery?
- The stratum corneum is a very effective and selective barrier
- The range of potential drugs that can be administered transdermally is very small
- Frequently, need additional penetration enhancers
- The API needs to be potent in low doses
37
What are the 3 key compartments of transdermal patches?
Backing layer, reservoir, adhesive
38
What is the role of the backing layer of transdermal patches? What is the function of the reservoir layer of a transdermal patch? What is the function of the adhesive layer of a transdermal patch?
1. Protects from damage
2. Holds the active pharmaceutical ingredient (API)
Controls the rate of drug release to the skin
3. Secures the patch to the skin
May contain additional penetration enhancers
39
What disease states reduce the skin's barrier function?
Ichthyoses, dermatitis, impetigo, eczema, psoriasis, inflammation
40
What is meant by 'zero-order' drug delivery in transdermal patches?
Constant drug release rate
41
In what order is permeability observed across ethnic groups?
Afro-Caribbean < Asians < Caucasians < Hispanics
42
Why is transdermal drug delivery best avoided in diseased skin?
It can lead to overabsorption, causing ADRs
43
Which skin layer's barrier nature reduces in conditions like ichthyoses, dermatitis, and psoriasis?
Stratum corneum
44
What are the advantages of transdermal drug delivery over oral administration?
- Peak and valley serum levels are avoided.
- First-pass metabolism is avoided.
- Less frequent dosing regimens are needed.
- Reduced variability between patients.
- Easy accessibility and large surface area.
- Non-invasive, increasing patient compliance.
45
What are the disadvantages of transdermal drug delivery?
- Stratum corneum is a selective barrier.
- Small range of potential drugs (low MW, high lipid solubility).
- Need for penetration enhancers.
- API needs to be potent in low doses.
46
What protects the adhesive layer of a transdermal patch during storage?
Release liner
47
What is the driving force for percutaneous absorption in transdermal patches? Why can an excess of non-dissolved drug be advantageous in transdermal patches worn for a week?
Concentration of soluble drug in the vehicle
Maintains a constant dissolved drug concentration over time
48
Name the two methods of formulating transdermal patches to maintain drug release for up to a week
What happens to non-dissolved drug in a transdermal patch as the dissolved drug is absorbed?
Reservoir and matrix
Become dissolved to maintain equilibrium
49
What are the key features of a reservoir transdermal patch?
- Drug layer is a separate liquid compartment.
- Sandwiched between backing and adhesive layers.
- Leak-proof rate-limiting membrane.
- Achieves zero-order delivery.
50
Why should reservoir patches not be cut?
To maintain the integrity of the drug reservoir
51
What are the key features of a matrix transdermal patch?
Drug layer is a semi-solid matrix.
Drug dispersed within a polymer matrix.
Polymer matrix controls drug release rate.
52
When are matrix and reservoir formulations often used?
When drug is incompatible/insoluble in the adhesive
53
What advantage does transdermal offer over semi-solid formulations?
No risk of incorrect dosage application
54
Describe the structure of a drug-in-adhesive transdermal patch.
Drug is incorporated within the adhesive layer.
Consists of a protective film, drug-containing adhesive, and backing layer.
55
For what kind of drugs are drug-in-adhesive patches normally used?
Drugs capable of readily permeating the skin
56
Name a drug used in a drug-in-adhesive patch
What is a limitation of drug-in-adhesive patches compared to reservoir or matrix patches?
Lidocaine
Shorter period of action
57
What are the brand names of nicotine patches? Over what period of time do nicotine patches release nicotine?
NicAssist, Nicorette, Nicopatch, Nicotinell, NiQuitin
16 or 24 hours
58
Give some brand names of estradiol patches.
For what conditions are estradiol patches used?
How long does an estradiol patch last?
Evorel, Progynova TS, FemSeven Sequi, Estradot
Menopausal symptoms and osteoporosis prophylaxis
24 hours
59
What drug is contained in Scopoderm TTS? How long does a Scopoderm TTS patch last? What is Scopoderm TTS used for?
Hyoscine/scopolamine
72 hours
Motion sickness
60
What drug is contained in Durogesic DTrans?
Fentanyl
61
How long does a Fentanyl patch last? For what is Fentanyl used?
72 hours
Chronic pain
62
What distinguishes devices from regular drug delivery systems?
Sophisticated systems intended for specific applications
63
List locations where implants are surgically placed inside the body.
Can devices, inserts, and implants contain drugs?
Subcutaneous tissue, breasts, penis, heart, bones
Yes, may or may not
64
For what type of distribution can drugs in devices, inserts, and implants be intended?
By what route are drugs most commonly administered to the eye?
Local or systemic
Drops
65
Why is less than 10% of topically administered drug dose absorbed in the eye? What can happen to the drug that is not absorbed in the eye?
Due to tear turnover and drainage
Absorbed via highly vascular nasal mucosa, causing S/Es
66
What is latanoprost (Xalatan) used to treat? What is an adverse side effect of latanoprost?
Glaucoma
Chest tightness
67
Where are drug-containing ocular inserts placed? How can the use of inserts overcome safety concerns associated with ophthalmic drops? What do ocular inserts maintain in the precorneal fluids?
On the cornea, hidden below the eyelid
Controlled opthalmic drug delivery
Relatively steady drug concentrations
68
What process allows drug diffusion across the cornea when using ocular inserts? How are ocular inserts affected by nasolacrimal drainage and tear flow compared to drops?
Maintaining drug concentration
Less affected
69
What is the primary factor controlling skin permeability (P)?
If a drug diffuses slowly through the stratum corneum, what is the equation for permeability (P)? If a drug diffuses quickly through the stratum corneum, what is the equation for permeability (P)?
Stratum corneum
P = KD/l
P = D/l
70
What is the level of systemic absorption of ocular inserts compared to drops?
Minimal
71
List the types of materials that ocular inserts can be made from. List the subtypes of insoluble ocular inserts.
Biodegradable, non-biodegradable, soluble, insoluble, erodible
Diffusional, osmotic, contact lens
72
What drug is contained within the Ocusert drug reservoir? What is the purpose of the white annular ring on the Ocusert?
Pilocarpine HCl in alginate gel
Allow patient positioning
73
Describe the structure of Ocusert.
- Drug reservoir (pilocarpine HCl in alginate gel).
- Sandwiched between two release-controlling membranes.
- Encased by a white annular ring.
74
How long does Ocusert release drug for? What condition is Ocusert used to control?
7 days
Increased intraocular pressure of glaucoma
75
What is the composition of Lacrisert? What condition is Lacrisert used to treat? What size is the Lacrisert insert?
Hydroxypropyl cellulose (HPC)
Dry eye syndrome (DES)
<4 mm long and <1.5 mm in diameter
76
How does Lacrisert work to treat dry eye syndrome? How long does Lacrisert take to dissolve?
Stabilises and thickens the tear film
6-8 hours
77
What causes the large value for the diffusion path length (l)?
What does the diffusion path length (l) value represent?
Torturous pathway through intercellular spaces
Distance to upper capillary region of dermis
78
How are drugs released from suppositories? For whom are suppositories typically used?
Base softens, melts, or dissolves
Infants, small children, and unconscious patients
79
What are the two main classes of base/vehicle used in suppositories?
Glyceride-type fatty bases and water-soluble bases
80
What factors affect the bioavailability of suppositories?
Retention time in the cavity.
Size and shape.
Melting point.
81
On what does drug release and the onset of drug action depend?
Liquefaction, dissolution, and drug diffusion
82
What are the desirable properties of a base/vehicle for suppositories?
- Melt, disperse, or dissolve at body temperature.
- Non-irritating.
- Physically and chemically stable.
- Pharmacologically inert.
- Compatible with a range of drugs.
- Ease of handling for production.
83
What is the usual weight range of rectal suppositories? What percentage of drug content do rectal suppositories usually contain? What are rectal suppositories usually intended for?
1-4g
0.1-40%
Systemic drug action
84
What is urethral suppositories typically used for? What drug is delivered by MUSE?
Treat severe erectile dysfunction
MUSE (Medicated Urethral Suppository for Erection)
Alprostadil
85
What is Alprostadil chemically identical to? What is Alprostadil's mechanism of action?
Prostaglandin E1 (PGE1)
Vasodilator
86
Why does local action via vaginal administration allow for smaller doses? Why can some drugs given intravaginally have higher bioavailability compared to the oral route?
Reduced absorption and systemic distribution/toxicity
Avoidance of first-pass metabolism
87
What hormones are contained in NuvaRing? How long does NuvaRing provide hormone release for? What is the daily release of ethinylestradiol from NuvaRing? What is the daily release of etonogestrel from NuvaRing?
Etonogestrel (progestogen) and ethinyl estradiol (oestrogen)
3 weeks
15 μg/24 h
120 μg/24 h
88
What is the purpose of vaginal rings? What are the approximate dimensions of vaginal rings?
Controlled release of drugs to the vagina
4 mm thick and 5.5 cm in diameter
89
What hormone does Estring release? What is Estring used to treat? What is the release rate of estradiol from Estring? How long does Estring release estradiol for?
Estradiol
Vaginal atrophy
7.5 μg/24 h
3 months
90
What hormone does Femring contain? What is Femring used to treat? How long is the release period for Femring?
Estradiol acetate
Vaginal atrophy and hot flushes
3 months
91
How do IUDs work to prevent pregnancy?
Preventing fertilisation of the egg by the sperm.
Inhibiting tubular transport.
Preventing implantation of the blastocyst.
92
Why are hormone-containing devices used in the uterus? What are the three main types of IUDs?
For hormonal effects such as menorrhagia
Inert, copper-based, or hormone-containing
93
How do copper-based IUDs prevent contraception? What is a side effect that is linked to copper-based IUDs?
How do copper-based IUDs prevent contraception?
Release copper into the uterine mucosal microenvironment
Increased uterine bleeding
94
How do hormone-containing IUDs affect hormone levels? What hormone do hormone-containing IUDs usually contain?
Provide lower systemic and higher local progestogen levels
Progestogen
95
What is the initial release rate of levonorgestrel from Mirena? How long is Mirena effective for?
20 μg/day
Up to 5 years
96
How long is Levosert designed to release levonorgestrel for?
Up to 3 years
97
How long is Jaydess effective for? What is the levonorgestrel content in Jaydess?
3 years
13.5mg
98
What type of drug delivery device is Progestasert? What is the purpose of barium sulphate in Progestasert? What is suspended in silicone oil in Progestasert? What material covers the reservoir in Progestasert?
Reservoir controlled drug delivery device
To make it radiopaque
Progesterone and barium sulphate
Ethylene vinyl acetate copolymer
99
What material is the horizontal bar of Progestasert made of? What is the daily release of progesterone from Progestasert? How long does Progestasert release progesterone for?
Polyethylene
65 μg
1 year
100
What are the steps of drug release from Progestasert?
1. Dissolution of progesterone in the silicone oil.
2. Followed by diffusion through the silicone oil to the inner surface of the polymer.
3. The drug partitions into the ethylene vinyl acetate copolymer.
4. It must then diffuse through the polymer, which acts as the rate-controlling membrane, to the biological interface.
5. It then partitions again into the biological fluid.
101
What is microneedles promising for? What is the typical length of microneedles? How do microneedles facilitate drug delivery?
Transdermal delivery system for therapeutic proteins
0.1-1mm
Create micron sized pores in the skin
102
Why do microneedles improve patient adherence? What are the three types of microneedles?
Painless (do not penetrate deep enough to trigger pain receptors)
Solid, hollow or dissolving
103
What are the characteristics of solid microneedles?
Easier to achieve full insertion & strong
Need to be disposed of as sharps waste
Can be incorporated into patches applied to the skin
104
What are the two ways solid microneedles can be used? How are drug-coated solid microneedles designed to deliver drugs?
As penetration enhancers
Coated in the drug
- Undergo dissolution upon insertion into the skin
105
What have drug-coated solid microneedles been shown to deliver for osteoporosis treatment?
Parathyroid hormone
106
How do hollow microneedles deliver drugs?
Infused through bores in the MN
107
What are the characteristics of dissolving microneedles?
Composed of water-soluble polymers loaded with drug
Difficult to fully insert into skin
Mechanically weak
108
Why is incomplete insertion a problem with dissolving microneedles?
It limits drug delivery efficiency
109
How do solid microneedles work as a pre-treatment for drug delivery?
Drug can diffuse through residual holes in skin
110
How do drug-coated microneedles deliver drugs into the skin? How do drug-loaded dissolving microneedles release the drug?
The drug coating dissolves off the microneedles
Upon microneedle dissolution
111
What is injected into the skin using hollow microneedles?
Liquid formulations
112
What effect did influenza vaccines delivered via microneedles demonstrate in the elderly? Why is vaccine effectiveness increased in the skin when using microneedles?
Increased immunogenicity
Highly immunoresponsive environment in the skin
113
How is a drug-containing implant usually prepared? What is the purpose of a drug-containing implant? How is the drug usually released from an implant?
By compression or melting
Provide drug-delivery at a desired rate
By diffusion or dissolution
114
What is the matrix or reservoir that the drug is released from made of?
Polymeric matrix or a reservoir
115
How else can drug release be controlled from an implant?
By the degradation of the polymer
116
What are drug-eluting stents designed to prevent?
Restenosis
117
What are urological implants at risk of? What is work ongoing on preventing for urological stents?
Infection and biofilm formation
Encrustation
118
How do dental implants normally combine with? What is injected into the periodontal cavity and forms a depot which releases doxycycline?
Prophylactic antibiotic treatment
Atridox
119
What does Vitrasert treat? What drug does Vitrasert release? What drug does Retisert release? What does Retisert treat? How long does Retisert treat for?
AIDS-related cytomegalovirus (CMV)
Ganciclovir
Flucoinolone acetonide
Chronic non-infection uveitis
Over 30 months
120
What length is the contraceptive implant? How long do contraceptive implants last? What does Nexplanon contain? How long does Nexplanon have to be removed after?
4cm
6 months to 7 years
Etonogestrel (68mg)
3 years
121
What is Norplant made of? How much levonogestrel does Norplant release? How long does Norplant last for?
Levonogestrel is a solid dispersed in a silicone matrix
30 μg per day
Up to 7 years
122
What is Gliadel® wafer a locally acting chemotherapy for? What percentage of carmustine is contained in Gliadel® wafer? How is Gliadel® wafer administered?
Gliomas
3.85%
Implanted in the resection cavity
123
What does Gliadel® wafer interfere with? How much BCNU do Gliadel® wafers supply in a controlled release? How long does Gliadel® wafer supply a controlled release of BCNU for? What is the survival benefit of Gliadel® wafers?
DNA synthesis and repair of cells
7.7mg
5 days
Improve median overall survival
124
What release times do reservoir systems typically offer? What release mechanisms are there? What do release mechanisms depend on?
Longer release times than tablets
Diffusion / erosion / osmotic
API characteristics
125
How can drug release be controlled from a reservoir implant? What is the location of ophthalmic implants?
By a rate-controlling membrane
Intravitreal
126
Where is Atridox injected?
Peridontal cavity
127
Why is physicochemical stability important in solid dosage forms?
To ensure adequate drug bioavailability
128
According to the British Pharmacopeia, what tests are carried out on solid dosage forms?
Uniformity of weight, dissolution and disintegration
129
What non-British Pharmacopeia tests are conducted on solid dosage forms?
Hardness, moisture content, stability and friability
130
What are the stages of a drug leaving a tablet?
Disintegration
Deaggregation
Dissolution
131
What must occur before absorption can take place?
A tablet must disintegrate and dissolve
132
What influences the rate of disintegration, dissolution, and absorption? What properties of a drug influence disintegration, dissolution and absorption?
Excipients in the tablet formulation
Physicochemical properties, stability, compactibility, site and extent of absorption and dose
133
What happens during disintegration? Why is disintegration evaluated? Is a max time for disintegration specified?
Tablets break into granules and particles
To ensure drug availability for dissolution
Yes, for each tablet
134
How do disintegrants work? What is the impact of disintegrants increasing the effective surface area?
By bursting tablets and promoting water ingress
Promotes rapid release and dissolution
135
How does swelling facilitate disintegration? What does the disintegration test determine?
It pushes apart adjoining particles
Whether tablets disintegrate within a prescribed time
136
For disintegration testing purposes, what does complete disintegration mean? Are disintegration tests directly linked to bioavailability?
A soft mass with no firm core
No, only indirectly
137
During testing, what should the wire mesh and basket be in relation to the fluid? What is important about the upward and downward stroke? How many dosage units are initially placed in the disintegration test?
Wire mesh 15mm below surface, basket 25mm from bottom
They should be equal times with smooth transition
1 in each of 6 tubes
138
What indicates successful disintegration in the test? If one dosage unit fails, how does the procedure continue? How many dosage units must disintegrate to meet test requirements?
All dosage units have disintegrated completely
Repeat the test on 12 additional units
Not less than 16 of 18
139
What is dissolution? What happens when a drug 'dissolves'?
Solid phase goes into solution phase
Particles separate and mix with liquid
140
What is the typical rate-limiting step in drug absorption?
Dissolution
141
What factors dictate the overall dissolution process? How is the rate of dissolution of a drug tested? What do dissolution media represent?
Solubility, ionisation, surface area
In vitro by dissolution test
Environments that the drug will experience
142
What is the pH of simulated gastric fluid (SGF)? What is the pH of simulated intestinal fluid (SIF)?
1.2
6.8
143
What is the composition of simulated gastric fluid (SGF)?
NaCl
Conc. HCl
Pepsin
Deionised water
144
What is the composition of simulated intestinal fluid (SIF)?
KH2PO4
NaOH
Pancreatin
Deionised water
145
What is needed to determine sink conditions?
Saturation solubility of the drug
146
How much larger should the volume of the medium be than the volume present in the saturated solution?
At least 3 times, ideally 5-10 times
147
What removal rate and GI fluid volume should testing mimic?
Removal rate of dissolved drugs by absorption
148
What type of SDF is USP Type I & II useful for? What care should be taken when placing the dosage unit in the apparatus? From where should a specimen be withdrawn during dissolution testing?
Immediate-release oral SDF
Exclude air bubbles
Midway between surface and top of basket
149
Dissolution testing:
How far from the vessel wall should the sample be taken? What must be done when multiple sampling times are specified? What must be done if this step is not necessary?
No less than 1cm
Replace aliquots with fresh dissolution medium
Correct for volume change
150
If the dissolution medium is a buffered solution, what adjustment should be made?
Adjust pH within 0.05 units
151
What is USP Type III apparatus? What are USP Type III and IV apparatus used for? What should be done with the vessel for the duration of the test for the Type III apparatus? What is USP Type IV apparatus?
Reciprocating cylinder with mesh base
Modified-release oral SDF testing
Keep vessel covered with evaporation cap
Flow-through cell
152
What does the Noyes-Whitney equation describe?
Dissolution of an API
K = D/h
D = coefficient of API
h = thickness of diffusion layer
153
What should be done with the aliquot withdrawn for analysis during dissolution testing?
Replace with equal volumes of fresh medium
154
What factors influence dissolution rate?
- Drug solubility
- Viscosity
- Diffusion layer thickness
- Sink conditions
- pH of the dissolution medium
- Particle size & surface area
- Crystalline structure
- Temperature
- Surfactants
155
How does increasing viscosity affect the dissolution rate in a diffusion-controlled process? What is the diffusion layer? What does the diffusion layer represent in the Noyes-Whitney equation?
Decreases dissolution rate
Thin, stationary film saturated with API
Equilibrium solubility of the drug
156
How does an increase in temperature affect the solubility of a solid in most cases?
Increases solubility
157
What type of process is enthalpy for dissolution? Why does heating the solution result in more rapid dissolution?
Endothermic
More energy to break solute-solute bonds
158
What steps are included in drug release?
Diffusion, disintegration, deaggregation, dissolution
159
What factors must be understood to design a controlled-release delivery system?
- Drug concentration
- Aqueous solubility
- Molecular size
- Crystal form
- Protein binding
- pKa
160
What profiles are drug dissolution and release usually? What negative effects can burst release have? In what situations are burst releases favorable?
Zero- or first-order release
Local or systemic toxicity, wasteful of drug
Wound treatment, encapsulated flavors, targeted delivery
161
What does burst release lead to?
Higher initial drug delivery
162
Where is zero-order release usually seen? What is a key factor in the Noyes-Whitney equation for first-order release?
Non-disintegrating dosage forms
Saturation solubility
163
When is the driving force for dissolution greatest?
Under sink conditions
164
What do coating materials provide? What are coatings used for? On what type of tablets are coatings NOT used?
Physical barrier
Prevent decomposition, minimize unpleasant taste
Buccal, sublingual, chewable
165
What are the uses of coatings?
1. Palatability (increased surface smoothness in mouth)
2. Minimise unpleasant taste (usually occurs due to dissolution in mouth)
3. Stability of APIs (may be degraded by light or atmospheric oxygen)
4. Safety – keeps highly potent compounds in core and therefore allows safe handling
5. Visual appeal
6. Control of release properties
7. Anti-counterfeiting (tracer compounds in coating material)
166
What are the types of coated tablets?
Sugar-coated
Film-coated
Modified-release coatings
Extended release (sustained & controlled release)
Delayed release (Enteric-coated)
167
What are sugar coatings made of? How thick can sugar coatings be? What are film coatings made of?
Layers of sucrose
20 – 50% w/w of total tablet weight
Water-soluble or insoluble polymers
168
What are the layers of a sugar coated tablet?
Tablet core
Sealant layer
Sugar coat 1
Sugar coat 2
Sugar coat 3
169
What is a common fault in sugar coating? What is the cause of this? Why is there more standardisation in sugar coating compared to film-coating?
Cracking and splitting of the coat
Excess residual moisture
Sealant layer isolates the core
170
What are the advantages of sugar coating?
1. Utilises inexpensive and readily available raw materials which are widely accepted - no regulatory problems.
2. For high humidity climates, it generally offers a stability advantage over film coated tablets.
3. Results are aesthetically pleasing and have wide consumer acceptability.
4. Tablet cores may be softer than those demanded by film coating, especially those for aqueous film coating – easier manufacturability.
171
What improves the flexibility of the film coating? What do film coatings contain?
For a good film coating, adhesion to tablet should be what?
Plasticiser
Polymer, plasticiser, pigment/opacifier and solvent/vehicle
Stronger than cohesive forces
172
What needs to be balanced for a good film coating? What increases cohesive forces? What is needed to form a good film?
Tensile strength & internal stress
Adhesion
Enough plasticiser, correct polymer choice
173
What are the vast majority of the polymers used in film coating? What shows chemical similarities to the polymer?
Cellulose derivatives, acrylic polymers
Plasticiser
174
What does modified release include?
Extended-release
Controlled-release
Sustained release
Delayed-release
Enteric-coating
175
What do modified release formulations utilise?
Polymers
176
What aspects of release do coatings control in modified release?
Diffusion
Polymer erosion
Osmotic effect
177
Why should ROS hydromorphone ER not be taken with alcohol? Why should Rivaroxaban be taken after food? What percentage bioavailability does Rivaroxaban need when taken with food? What can Rivaroxaban tablets be mixed with if the person has difficulty swallowing?
It can produce additive sedative effects
Due to its pharmaceutical properties and bioavailability
≥ 80%
Water or apple puree
178
Why are slow-release and extended-release Nifedipine preparations not interchangeable? What letters might slow-release Nifedipine tablets have after the brand name? According to NHS guidance, what is Nifedipine sensitive to?
Different release rates affect drug action
XL, LA, SR, MR
Light
179
How should Nifedipine capsules or tablets be taken? Why is it important to stick to the same brand of slow-release nifedipine? What might you notice in your poo when taking slow-release nifedipine?
Swallowed whole with water
Different brands may be different
A "whole tablet" - tablet coating
180
Why must Dabigatran capsules not be opened?
It increases bioavailability significantly
181
Why does GTN spray and sublingual delivery result in rapid absorption? What does sublingual delivery of GTN allow the API to avoid?
High vascularisation within the mouth
First-pass metabolism
182
What does bioequivalence of two formulations assume? What is required for two drug products to be considered pharmaceutical equivalents?
They will provide the same therapeutic effect
Identical amounts of the same active ingredient
183
When are two drugs considered pharmaceutical alternatives? How do pharmaceutical alternatives achieve bioequivalence?
Identical therapeutic moiety, but not necessarily same amount
They become available at the site of action
184
What does bioavailability refer to?
Fraction of drug that reaches blood supply
185
What factors can affect bioavailability?
The crystal form of the drug
Dosage form (tablet or capsule)
Variation in constituents (excipients)
186
What should be checked if there is any change to the manufacturing, formulation, or storage processes?
That bioavailability remains the same
187
What must be established for generic formulations regarding bioequivalence? What data is collected to assess bioequivalence?
Bioequivalence in healthy volunteers and similar dissolution
Pharmacokinetic data
188
What does the Biopharmaceutics Classification System (BCS) provide? What factors are considered in the BCS?
A scientific basis for deciding when tests are needed
Permeability & solubility
189
What does 'Biowaiver' mean? Which BCS classes are current FDA and European Medicines Agency practice limited to for biowaivers?
In vivo bioavailability/bioequivalence studies may be waived
Class I and Class III
190
What could be adopted as the surrogate basis for bioequivalence instead of in vivo studies
Dissolution test
191
What dissolution characteristics must a product demonstrate for BCS class I and III biowaivers? What is the minimum amount of dosage units needed to support a biowaiver?
Rapid or very rapid dissolution
12
192
How many different buffers should dissolution tests be run in? What pH should the buffers in dissolution tests normally be?
3
1.2, 4.5 and 6.8
193
What do the OGD and FDA encourage applicants to do for immediate release generic products containing BCS class I drugs? What documentation is required with a waiver request for BCS class I drugs?
Request a waiver of in vivo BE studies
High solubility, high permeability, stability, rapid dissolution
194
When are BCS-based biowaivers NOT applicable?
Narrow therapeutic range drugs
Products designed to be absorbed in the oral cavity
