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`
`APPENDIX
`
`CONTENTS
`
`1.
`
`API Dissolution Analysis
`
`2.
`
`3.
`
`4,
`
`5.
`
`6.
`
`7.
`
`8
`
`9
`
`‘1.1.
`1.2
`1.3.
`14
`
`Dissolution in 0.1N HCl (UV and HPLC)
`Dissolution in Phosphate buffer pH 6.8 (UV and HPLC)
`Dissolution in DJ Water (UV)
`Dissolution in Buffer pH 4.5
`
`Intrinsic Dissolutions
`
`API Related Substances (Comparison to Cilag)
`
`Finished Product Related Substances
`
`Freeze-dried complexes FB Related Substances
`‘
`
`Formulations based on Fludaribine
`41
`Fludaribine Formulation: RDT0385
`4.2
`Enteric-coated tablets: (Fludaribine Formulation). RDT0385b
`4.3
`20% Carbomer Formulation: RDT0398a
`5.4
`Cyclodextrin Formulation: RDT0398b
`
`Buccal and granule Formulations using Diclofenac as API
`6.1
`Buccal / Sublingual
`°
`6.2
`Mucoadhesive granule for HGC fill
`6.3.
`Mucoadhesive Direct compression tablet
`6.4
`Tablet within a tablet formulation:
`
`Phase solubility testing
`
`Cladribine freeze-dried Cyclodextrin complexes
`91
`Cyclodextrin Complex Formulations for Buccal/Sublingual Dosage forms
`9.2. Manufacturing Process
`9.3.
`Physical Parameters
`9.4
`Dissolution profiles of Cladribine freeze-dried buccal tablets in water and salivary
`buffer
`Results
`9.5
`9.6 Dissolution and Degradation profiles of Cladribine freeze-dried Cyclodextrin buccal
`tablets in 0.1N HCl
`
`
`
`
`
`API ANALYSIS
`
`
`
`1.1 Dissolution in 0.1IN HCl
`
`Initial analysis of active by UV showed 10% degradation of API over 2 hours.
`Following from this HPLC analysis of active in 0.1N HCL showed degradation of Cladribine
`and growth of Impurity D (RRT 0.701). Approx 3% Cladribine remaining after 120 minutes
`dissolution.
`
`Dissolution of RDT0385 in 0.1NHCI
`
`%Dissolved
`
`—@— % Cladribine
`
`—m— % Impurity D
`
`60
`
`“90
`
`Time (mins)
`
`O21teen jennmentees
`
`
`
`
`Q“_
`oo
`2c
`2
`3sOo
`|
`i
`.
`|
`|
`=f SO
`wW
`ee
`a
`i
`i
`1
`eneeDgteccap
`een iotn
`0.0000~pneernsinenninrernnmrnettl abe - ats” RoeS weetnfenSyne
`0.0001
`|{
`
`2
`
`x
`
`}
`
`0.00027erreeeiesEppeesemprrney eee
`06
`2.00
`4.00
`6.00
`oO
`Minutes
`
`7
`10.00
`
`enmamnnnngep
`42,00
`
`teGee+
`14.03
`
`at
`
`Chromatogram of Cladribineafter 2 hours dissolution in 0.1N HCl. Growth of impurity
`D at retention time 5.936 minutes
`
`
`
`
`
`1.2
`Dissolution in Phosphate buffer
`pH 6.8 HPLC
`102% dissolved after 2 hours. No observed degradation after 5 hours. No increase in related
`substances.
`
`% Cladribine / % Impurities Dissolution in Buffer pH 6.8
`
`
`420.000
`400.000 > .
`
`.
`
`.
`
`
`
`80.000
`
`
`
`
`60.000
`
`%Assay
`
`40.000
`
`
`
`20.000
`0.000
`—@— % Cladribine
`
`—e— % Impurities
`
`
`1 Hour
`
`2 Hours
`
`3 hours
`
`4 Hours |
`
`5 Hours
`
` Timepoint (Hours)
`
`LC
`Dissolution in DI Water
`13
`102% dissolved after 2 hours. No observed degradation after 5 hours. Increase in assay of
`Cladribine after 72 hours due to evaporation ofmedium. Noincrease in related substances
`
`% Cladribine / % Impurities Diss in H.O
`
`
`
`
`140.000
`
`
`
`420.000
`
`—~—e— % Cladribine
`
`
`100.000 ee
`—w— % Impurities
`%Assay
`
`
`
`
`
`4 Hour
`2 Hours
`72 hours
`
`
`Timepoint (Hours)
`
`
`80.000
`
`60.000
`
`40.000
`
`20.000
`
`0.000
`
`
`
`
`
`
`1.4
`Dissolution in Buffer pH 4.5 (HPLC)
`
`102% dissolved after 2 hours. No observed degradation after 2 hours. Increase in impurities
`(0.1%) of Cladribine after 24 hours.
`
`%Cladribine / % Impurities Dissolution in Buffer pH 4.5
`
`120.000
`
`100.000 OO
`
`Timepoint (Hours)
`
`80.000
`
`60.000
`
`40.000
`
`20.000
`
`0.000
`
`4 Hour
`
`2 Hours
`
`3 hours
`
`24 Hours
`
`—@— % Cladribine
`
`—mi— % Impurities
`
`5
`
`
`
`
`
`
`
`2
`
`INTRINSIC DISSOLUTIONS
`
`Note:
`
`IDR of 0.1 mg/min/cm? correspondsto solubility of 1 mg/ml.
`Cilag estimate solubility of 5mg/ml in water
`
`IDR of API in DI water:
`IDR of Gamma-CD complex in DI water:
`IDR of HP-CD complex in DI water:
`
`0.3316 mg/min/em’
`0.6026 mg/min/em’
`0.8246 mg/min/em’”
`
`
`
`Intrinsic Dissolution of Cladribine API, HP-CD Complex and Gamma-CD
`
`y =0.8246x
`
`Complex in Di Water
`
`y =0.3316x
`
`_
`
`2 =
`
`5a
`
`a
`o &
`£54
`SE
`3CGC=
`c3
`
`3E
`
`Pad
`
`7
`
`6
`
`
`
`
`
`
`
`Time (Minutes)
`
`
`IDR of API in phosphate buffer pH 4.5:
`IDR of Gamma-CD complexin salivary buffer pH 7.0:
`IDR of HP-CD complexin salivary buffer pH 7.0:
`
`0.2395 mg/min/em’”
`0.6637 mg/min/em’
`0.8313 mg/min/cm”
`
`Intrinsic Dissolution of AP! in buffer 4.5 and HP-CD and Gamma-CDin
`salivary buffer pH 6.8
`
`s
`®o
`
`= 5
`
`tn
`Bem
`32S
`
`3a
`
`=
`a
`5
`
`8
`7
`
`6
`5
`
`4
`ns
`2
`4
`0
`
`y = 0.8313x
`
`y = 0.6637x
`
`4
`
`6
`
`@ API
`i HPCD Complex
`4 Gamma Complex
`
`
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`
`Time (minutes)
`
`
`
`
`
`3.
`
`API RELATED SUBSTANCES
`
`eteetcheersanaes
`
`
`
`
`
`Q.0007-;
`
`
`
`
`
`sue{2.824
`
`auenas>"
`
`OD snepaeamanngynatrgermmoney
`9.90
`
`4O
`
`Cilag Assay
`
`
`IVAX Assay
`
`
`
`2-Amino-2 deoxyadenosine
`(Impurity B)
`
`0.563
`
`0.200
`
`
`o.co02"4 9.00017}Badkedabthand
`TOTAL IMPURITIES NMT0.3%
`
` 0.060
`
`2-Chloro-adenine
`(Impurity D)
`
`2-Methoxy-2-deoxyadenosine
`(Impurity E)
`
`2-Chloro-9-(2 deoxy-a-D-
`ribofuranosyl)-adenine
`(Impurity F)
`
`Cladribine
`
`Unknown 1
`
`NMT 0.3%
`
`0.701
`
`<0.1
`
`0.002
`
`NMT 0.2%
`
`0.821
`
`0.200
`
`0.082
`
`NMT0.2%
`
`0.951
`
`<0.1
`
`0.01
`
`98% - 102%
`
`1.000
`
`99.8
`
`98.5
`
`Uninown Impurity RRT
`(Cilag RRT) = 1.85
`
`NMT 0.1%
`
`1.763
`
`NMT 0.2%
`
`1.85
`
`Impurity G
`
`NMT0.1%
`
`2.123
`
`RW4J-47753-000
`
`NMT0.1%
`
`RW4J-47754-000
`
`NMT0.1%
`
`3.877
`
`4,511
`
`NMT 1.0%
`
`0.6%
`
`0.088
`
`0.043
`
`0.056
`
`0.3%
`
`
`
`
`
`
`
`4.
`
`FINISHED PRODUCT RELATED SUBSTANCES
`
`Name
`
`RRT
`
`Specification
`
`RDT0385
`(Fludaribine
`formulation
`
`
` 2-Amino-2
`
`NMT0.3%
`deoxyadenosine
`(@mpurity B)
`
`RDT0398a
`(Carbomer
`formulation
`
`0.067
`
`RDT039
`(Cyclode
`formulat
`
`
`0.056
`
`0.059
`
`2-Chloro-adenine
`(impurity D)
`
`2-Methoxy-2-
`deoxyadenosine
`(mpurity E)
`
`2-Chioro-9-(2 deoxy-c-
`D-ribofuranesy])-
`adenine
`(Impurity F)
`
`0.701
`
`NMT0.3%
`
`0,821
`
`NMT 0.2%
`
`0.002
`
`0.083
`
`0.002
`
`0.093
`
`0.002
`
`0.076
`
`0.951
`
`NMT 0.2%
`
`0.010
`
`0.012
`
`0.009
`
`Cladribine
`
`1,000
`
`98% - 102%
`
`Unknown 1
`
`1.763
`
`NMT 0.1%
`
`Unlnown Impurity
`RRT (Cilag RRT)
`= 1.85
`
`NMT 0.2%
`
`Impurity G
`
`2.123
`
`NMT0.1%
`
`RWJ-47753-000
`
`3.877
`
`NMT 0.1%.
`
`RWJ-47754-000
`
`4.511
`
`NMT 0.1%
`
`96
`
`0.086
`
`0.001
`
`0.042
`
`0.049 —
`
`114
`
`0.101
`
`0.000
`
`0.050
`
`0.059
`
`90
`
`0.082
`
`0.000
`
`0.039
`
`0.047
`
`TOTAL
`IMPURITIES
`
`NMT 1.0% —
`
`0.33%
`
`0.38%
`
`0.24% ~
`
`
`
`
`
`5.
`
`ASSAY AND RELATED SUBSTANCES OF FREEZED DRIED COMPLEX RAW
`MATERIAL AND TABLETS
`
`
`Gammi—|HP-B-CD eee FD03 (5mg
`
`Identity|ChemicalName|RRT CD Raw Raw ‘cD| pcp
`
`
`
`Material
`Material
`Tablets)
`Tablets)
`
`
`
`ImpB|,2-Aanino2'® 0.19 oat|eoxyadenosine 0.54 0.28
`
`ne
`
`
`
`
`
`
`
`Imp D
`
`2-Chloroadenine
`
`<0.05
`
`top 4)
`
`2Metheny2s
`deoxyadenosine
`
`Imp F
`
`
`
`
`
`
`2-Chloro-9-(2’-
`deoxy-a-D-
`dbofurancsy!)-
`
`adenine
`
`
`
`
`
`
`0.83
`
`0.93
`
`
`
`Theoretical
`% Active
`in Complex
`
`
`
`
`
`Actual %
`Active in
`
`Complex
`Unknown
`
`
`
`
`
`
`.
`Cladribine
`
`Cladribine
`eS
`
`Not Known
`
`ND
`
`2.128
`
`2.293
`
`0.13
`0.12
`0.14
`
`
`0.13
`
`ND
`
`ND
`
`2.347
`
`2.353
`
`0.09
`
`4o616-o00|Not ®nown mp
`
`
`
`BoE 8
`Zzaleo|&
`y|6 UE
`
`
`
`)=
`.60
`
`1.56*
`<0.05
`<0,05
`
`' S°a
`Rw|-
`
`47753-000|Not ®nown ND
`i
`oO 2
`
`0.08
`
`0.06
`
`i
`
`=
`
`van
`
`own
`
`Not Known
`
`9
`
`ND
`
`Unknown
`
`Not Known
`
`Not Known
`
`4.63
`
`ND
`
`0.33
`
`Unknown
`
`BIE
`
`l l
`
`* To be investigated. Possible solvent or carryover.
`
`| \| b
`
`|||
`
`Peas mening bes. 11e@Sres Ze
`
`2. RAMEE ms
`
`AMMIAAAA
`
`
`
`
`
`SUMMARY
`
`Nodifferences observed in assay for related substances for API and any formulations.
`Recommended PDAanalysis on APIalso.
`
`6.
`
`FORMULATIONS BASED ON FLUDARIBINE
`
`Three 100g batches using Cladribine API have been manufactured using the following formulations:
`
`
`
`
`
`
`
`
`
`
`0.03
`3.24
`
`
`
`6.1 Fludaribine Formulation: RDT0385
`
`101.4%
`-
`e Assay
`100.5%, RSD = 3.17%
`-
`e« CU
`Max 91% 30 minutes.
`-
`e UV Dissolution (0.1N HCl)
`e HPLCanalysis carried out on dissolution in HC] showed breakdownof Cladribine into impurity
`D. Only 3% Cladribine remaining after 2 hours dissolution.
`UV Dissolution (buffer pH 6.8)
`-
`Slow release. 85% after 240 minutes
`UV Dissolution (Water)
`-
`Fast release. 101% after 2 hours.
`
`
`
`
`
`
`
`6.2
`
`Enteric-coated tablets:
`
`(Fludaribine Formulation). RDT0385b
`
`UV Dissolution in 0.1N HC] followed by buffer pH 6.8 - 7.0.
`7% dissolution after 2 hours in acid, (min 5%, max 18%). On addition of pH 7.0 conditions
`dissolution increased to 97% after 2 hours (min 84%, Max 107%). After 4 hoursin acid,
`dissolution was 116%.
`20% Carbomer Formulation: RDT0398a
`6.3
`
`Results mayberelated to tablet weighti.e. heavier tablet gives higher dissolutions
`
`Assay
`cu
`UV Dissolution (0.1N HCl)
`UV Dissolution (buffer pH 6.8)
`
`UV Dissolution (Water)
`
`-
`-
`-
`-
`
`-
`
`113.9%
`+ 105.7%, RSD = 6.4%. Oneresult at 123.1%
`Max 80%, 240 minutes. Slow release profile
`Slow release. 86% after 10 hours. 0.1%
`Carbomerinterference. Further HPLC analysis
`showspossible Carbomer peak at 4 —5 minutes.
`0.2% - 1.0%.
`Fast release. 97% after 2 hours.
`
`6.4
`
`Cyclodextrin Formulation: RDT0398b
`
`Cyclodextrin formulation is sub-potent due to extra Mag Stearate added. Estimated potency at 95%.
`
`Assay
`CU .
`UV Dissolution (0.1N HCl)
`UV Dissolution (buffer pH 6.8)
`UV Dissolution (Water)
`
`-
`o
`
`~
`
`89.9%
`83.2%, RSD = 3.3%
`Max 83%, 48 minutes. Degradation occurs.
`Max 76%, 1 hour. No Cyclodextrin interference
`Max 86% after 1 hour.
`
`SUMMARY
`
`Cladribine APIis acid labile. Formulation needed to avoid acidic stomach conditions.
`
`No degradation observedin water, buffer pH 4.5 and buffer pH 6.8
`
`APT IDR matches Cilag estimated solubility. Best IDR in water.
`
`Solubility issue in buffer pH 6.8. Dissolution values are less than assayresults.
`
`Solubility does not seem to be a problem in water. Dissolution results matching assay and CU.
`
`Fludaribine formualtion shows fast release in water andslow release in buffer pH 6.8.
`
`Carbomer formulation allows for slow release. Carbomer impurity ( approx 1.0%) present in
`chromatography.
`
`10
`
`
`
`
`
`
`
`Some spurious CU results (121%) indicating possible processing problems with Carbomer 974
`or high levels of Carbomer.
`
`e Possible potency issue with Cyclodextrin formulation. Only getting 90% assay and dissolution.
`Immediate release in buffer and water.
`
`7
`
`BUCCAL AND GRANULE FORMULATIONS WITH DICLOFENAC API
`
`Six batches using Diclofenac Sodium in place of Cladribine API were manufactured to explore the
`developmentof buccal / sublingual and mucoadhesivetablets as patentable cladribine formulations.
`
`Formulation:
`
`65.25 qf
`
`
`
`
`
`0.50"
`|
`0s0
`*Extra 0,5mg/tablet added to minimise picking.
`RDT0399c was manufactured as RDT0399a placebo.
`
`
`
`21.75
`
`19.88
`
`Physical parameters:
`
`‘Tt
`
`0399b
`
`Flat /Concave
`
`13"
`
`
`
`|135|ODF
`3.07
`:
`.
`3.10
`2min 34sec
`4min 45sec
`>15min*
`>15min**
`
`*Tablet formed a soft globular mass with adhesive properties
`** Tablet formed a globular mass with strong adhesive properties. Mass wasdry in centerafter 15
`mins.
`
`NOTE:
`
`Diclofenac has solubility problemsin 0.1N HCl.
`Diclofenac Na dissolves 16% - 20% in 0.1N HCL.
`
`ii
`
`
`
`
`
`TA
`
`Buccal / Sublingual:
`
`RDT0399a + RDT0399b:
`Manufactured using Sodium CMC at 2.5 — 5 % respectively.
`e UV Dissolution of approx 70% after 10 hours in simulated saliva solution. 68% dissolution after
`30 minutes.
`e Assay of 70%.
`®
`Noobvious reason for low results.
`e
`Poortaste from tablets. Possible Diclofenac Nataste. Recommend 2mgdrug formulation per 100
`mgtablet to inhibit possible taste issues.
`
`7.2___ Mucoadhesive granule forHGC fill:
`
`NOTE:
`
`Carbopol 71G mayoffer better flow properties due to its granular nature which may
`alleviate possible processing problems.
`
`RDT0399d:
`Manufactured using Carbopol 974P at 2.5%.
`e
`5% dissolution in 0.1N HCl after 2 hours. 97% dissolution after 3 hours in pH 7.0 buffer.
`
`RDT0399e:
`Manufactured using Carbopol 974P at 10%.
`e
`6% dissolution in 0.1N HCl after 2 hours. 91% - 99% after 3 hours in pH 7.0
`
`7.3
`
`Mucoadhesive Direct compression tablet:
`
`.
`RDT0399f:
`Manufactured using Carbopol 71G at 2.5%.
`e
`5% dissolution in 0.1N HCl after 2 hours. 76% after 3 hours in pH 7.0
`
`RDT0399¢:
`Manufactured using Carbopol 71G at 10%.
`e
`2% dissolution in 0.1N HCI after 2 hours. 90% after 3 hours in pH 7.0
`
`All tablet formulations flowed and compressed well.
`The granulated product produced a good strong granule. Milled through a 0.075 inch comil screen.
`
`1A
`
`Tablet within a tablet formulation:
`
`
`
`
`
`Outertablet coat used to protect Cladribine from acidic stomach conditions.
`
`Dissolution in 0.1N HCL followed by buffer pH 6.8. Tablets completely disssolved in acid (86% -
`95%) after 25 minutes. No advantage.
`
`8
`
`PHASE SOLUBILITY TESTING
`
`Table 1. Solubility of cyclodextrins in water (¢/100 ml)
`
`
`
`PROTOCOL FOR PHASE SOLUBILITY STUDIES OF CLADRIBINE IN PRESENCE OF
`CYCLODEXTRIN
`
`Reperted Solubility of Cladribine in Water is 5 mg / ml
`
`TABLE1
`
`
`
`
`
`
`SOLUTION
`Solution of CD,
`
`
`
`SYSTEMS
`800 meg in 4ml B.soln
`
`
`
`2ml B. Soln
`400 mg
`
`
`
`2ml B.soln, +2mlD.Water
`(200 mg)
`
`
`
`2misoin.B +2mlD.Water
`(100 mg)
`25 mg
`
`
`
`\D———séd Dh md gcln. C +2 m1 D.Water (50mg 25 mg
`
`
`E (25mg)*|25mg2misoln.D+2mlD.Water
`
`
`
`
`
`* Use only 2 ml of solution fortesting
` 0.0 mg
`[Fo
`2 ml D.Water
`F
`25 mg
`
`
`DRUG ADDED
`
`B
`
`Cyclodextrin
`B.soln. — Bulk Solution
`D.Water — Deionised Water
`Methodfor preparation.
`
`aeGe
`
`In screw capped vials take 2 m] Cyclodextrin solutions as mentioned in Table 1.
`Add respective quantity of drug in eachvial.
`Allow the samples to sonicate for 30 minutes.
`Removethe samples from sonicator and place on shakerfor 8 hrs.
`The sample after shaking is filtered to get clear supernant.
`Analyse the sample by UV at 265 nm wavelength.
`
`13
`
`
`
`
`
`
`
`RESULTS:
`
`
`
`aps
`
`Cladribine —HP betaCD
`
`CD Conc.
`(Trial A)
`
`
`
`Molar
`
`
`
`
`
`j
`
`
`
`
`Cladribine -HP betaCD +
`Cladribine -gama- CD
`HPMC(0.1%)
`(Trial C)
`(Trial B)
`
`
`0.0086
`
`0.132
`
`
`0.00] 2.610|0.00940.140
`
`
`
`
`
`0.018] 3.139|0.0110.169 0.1352 2.519 |0.0088
`
`
`
`
`
`
`0.035] 3.554|0.01246.191 0.175 3.262 . 2.852 10.0100
`
`
`
`
`
`
`
`0.1542|2.873 [0.0101
`
`
`
`
`
`0.1965|3.661 [0.0128
`P0285]0.514|9.581|0.0335|0.259|4.831|0.0169|0.4688|8.733
`
`
`
`
`
`
`
`
`.
`
`
`
`mg/ml
`
`
`
`|Molar c
`
`CD- Molar Cons.
`
`PHASE SOLUBILITY STUDIES
`
`
`
`CladribineMolarConc.
`
`0.071
`
`0.142
`
`0.285
`
`—@—HP-Beta-CD
`
`—i-— Gama-Cd
`
`—BHPCD+HPM
`CG
`
`Observations:
`
`Thebest solubility results are obtained with HP-beta CD as complexing agent.
`e
`e With HP-beta CD + HPMC (0.1%) results are similar to HP-beta CD , at higher concentration
`
`fine precipitation was observed in the vials at the end of the study.
`
`Absorbanceof this sample is low andindicates precipitation of solubised drug
`
`e Absorbance with Gama-Cyclodextrin is low as compared with HP-beta CD.
`
`‘e Baill park solubility of 9.581 mg/ml in comparison to 5 mg/mlsolubility with API alone.
`
`.
`
`14
`
`
`
`
`
`SUMMARY
`
`Cyclodextrin/Cladribine complex showed increased Cladribinesolubility
`
`Complex sentfor freeze-drying.
`
`Cladribine API groundto decreaseparticle size (10g)
`
`Process buccal and sublingual tablets using freeze-dried material
`Issues regarding taste and poorassay, dissolution on previous buccaltablets.
`Information on buccal formulation work in Miami.
`
`Continued investigation into oral dosage formulations:
`
`1. Tablet-within-tablet:
`High viscosity HPMCin outer formulation for protection against
`acidic stomach conditions.
`
`2. Soft gel capsule:
`10g API sent to Czechslovakia fortrials.
`
`3. Dry emulsion formulation:
`Dummy emulsion to be made with freeze-dried sample
`
`15
`
`
`
`
`
`9
`
`CLADRIBINE FREEZE-DRIED CYCLODEXTRIN COMPLEXES
`
`9.)
`
`Cyclodextrin Complex Formulations for Buccal/Sublingual Dosage forms
`
`
`
`
`
`|_1C130.
`
`0
`|Gamma-Ccb_|NA|213s
`13
`Gamma-CD
`N/A
`
`+Cladribine
`
`HPCD + Cladribine
`
`N/A
`1F290
`REO541|Magnesium Stearate
`
`
`9.2
`Manufacturing Process
`
`:
`
`Cyclodextrin FD / Complex
`
`(18 Mesh)
`
`Magnesium Sterate / Lactose pre-mix
`(40 Mesh)
`
`Turbula Mixer (5 min)
`
`Manesty Single station F-press
`( 220 mg, 10.0 mm round concave UP/ Flat Bevelled LP)
`
`e Flow and compressibility good forall fractions.
`
`OBSERVATIONS
`
`16
`
`
`
`
`
`Nopicking noticed
`
`9.3 Physical Parameters
`
`Average weight: A) 215 mg, B) 220 mg, C) 237mg, D)220mg.
`
`Average Hardness: 3- 4 Kp
`
`Thickness : 3.2mm - 3.4mm
`
`' Disintegration Time : 6 — 7 minutes ( Water/ Simulated Saliva Buffer)
`
`Dissolution profiles offreeze-dried buccal tablets in water and simulated salivary
`9.4
`buffer solution
`
`
`
`Dissolution of Cladribine freeze-dried Cyclodextrin-complex tablets in D! water
`and simulated salivary buffer pH 6.8. Comparison to Fludaribine formulation
`tablets (RDT0385).
`
`—@— RDT0385 (water)
`~f4— HPCD (water)
`aud Gamma (water)
`~—gé— HPCD (buffer)
`-~K-- Gamma (Buffer)
`—@— RDT0385 (buffer 6.8)
`
`5xo8=w2~5 Z
`
`
`
`30
`
`40
`
`Time (minutes)
`
`Simulated Saliva Solution: 2.38¢ Na,HPQ,, 0.19g KH,PO, and 8g NaClin1litre of distilled water, pH 6.75, at 37°C
`
`9.5
`
`Results
`
`Increased Dissolution time.
`HP-CD. 100% dissolution in salivary buffer after 10 minutes.
`Gamma-CD. 100% dissolution in salivary buffer after 15 minutes
`
`HP-CD. 100% dissolution in water after 10 minutes.
`Gamma-CD. 100% dissolution in salivary buffer after 15 - 18 minutes
`
`Increased Solubility.
`
`
`
`
`
`100% dissolution attained for both tablet types in both buffers. Comparison to Fludaribine
`formulation dissolution in water and buffer show faster dissolution and greater solubility.
`
`Dissolution and Degradationprofiles of freeze-dried Cladribine-Cyclodextrin
`96
`complex buccal tablets in 0.1N HCI
`
`
`Dissolution/Degradation of HP-CD tablets and Gamma-CDtablets in 0.1N
`Hydrochloric Acid
`
`cenitni
`
`—
`
`
`
`
`
`
`
`
`—@-- Dissolution od FD03 (HFCD)
`—m— Degradation of FDO3 (HPCD)
`~~Dissolution of FD02 (Gamma)
`~~~ Degradation of FD02 (Gamma)
`
`
`
`
`‘ Time (minutes)
`
`
`
`Degradation ofCladribine peak to Impurity D ebserict 10— 15% after 10 minutes. 100%
`
`dissolution after 10 — 15 minutes.
`
`Byoptimising complexation, we can further inhibit acidic degradation of the drug in the stomach
`whilst increasing drug availability for absorption.
`
`
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