2015-03-26 Thesis Overview

PHARMACEUTICAL TECHNOLOGIES 1

ALEX WALL

Characterisation of Roller-Compacted Ribbons and Tablets with Terahertz Time-Domain Pulsed Imaging

PHARMACEUTICAL TECHNOLOGIES

Background

Dry granulation comprises three integrated steps of blending, roller-compaction (or slugging)

and milling.

The roller compaction stage produces ribbons of the blended material which are then milled

to produce granules of controlled size distribution (Inc. fines) and porosity, as these

parameters impact flow and compaction properties.

The target quality attributes of the ribbon are content uniformity and uniformity of the

porosity/density profile of the ribbon.

Content uniformity is controlled in the blending stage and porosity/density is controlled by

the RC stage.

One feedback loop for controlling the density of ribbons emerging from the RC process is to

control the roll pressure (as our surrogate for density) by adjusting auger speed to account for

inherent fluctuations in feed density.


Aim & Objectives

Aim: To research the application of THz imaging for determining the density and thickness of RC ribbons.

There are four area of this study:

1. OEM glass slides: Initial validation of 3 time-domain terahertz methods* on. 2. Tablets: Optimising the TD analytical methods on. (A 4th frequency-domain (FD) THz method was

required**).3. Prediction of mechanical strength (RTS) as a further use of the FD THz method**.4. RC Ribbons: Evaluate our aim of predicting parameters of density and thickness.

* The terahertz principle time-domain methods include:a) TD transmission optical-time-delay analysis.b) TD reflection amplitude coefficient. c) TD reflection optical-time delay analysis, andA frequency domain method chiefly used as a comparator method to the TD methodsd) FD spectral extraction of RI’s.


𝑅𝐼=𝑐𝑜(𝑚/ 𝑠) /𝑐𝑠𝑎𝑚𝑝𝑙𝑒(𝑚/ 𝑠)𝐸𝑞𝑢 .1

The optical time-delay methods require:1) A reference time delay measurement.2) Inserting an analyte, a proportion of the signal is either transmitted, slowing c (see Equ. 1:) , or reflected at the surface (see Fig 2. @ times <20ps).

This provides two options to measure RI:1. Optical time-delay: see TD waveform plot in transmission; Fig 1.• RI has a linear trend to density, and sensitive to chemical composition.• The ref max(t) against the 1st (attenuated) silica peak (Fig 1. @ ~10 ps), • allows Equ. 2 for RI. If a 2nd is observed, (as at ~22 ps), the signal has bounced internally and exited the posterior to give a Fabry-Perot echo. This is analogous to Fig 2. (at 20-30 ps).

2. The proportion of signal reflected; Fig 2 & 3.𝑅𝐼=1+¿

Summary of TD methods (demonstrated with glass slides) to chiefly extract RI

Fig 1: TD waveform in transmissionTime-domain methods

305 310 315 320 325 330 335-4-202468

Internal Delay. ID

(t)

Signal De-lay, SD (t)

Silica Ref. Pulse

Optical Delay, ps

THz

E-Fi

eld

×103

, a.u

.

02468

10

AUC = 0.48 I (t)

AUC = 1.48 I(t)

Ref. Intensity Silica Intensity

Optical delay-time, ps

THz

Inte

nsity

10

, au

Fig 2: TD waveform in Reflection

• The proportion of the reflected signal surface (Fig 2 ~20ps) compared with a ref. of full reflection is treated with the Hilbert transformation = signal intensity.• The function simulates a B-Field for enhanced Intensity (t). Then the area under the intensity curve (at the substrates interface: highlighted) provides coefficients that when applied to a simplified Fresnel amplitude reflection coefficient, yield reliable RI’s that are fit for purpose. (Equ. 4)• Now that a RI can be generated, so can thickness.𝑟𝑝=

𝐴𝑈𝐶 (𝑠)(0.48)𝐴𝑈𝐶 (𝑟 )(1.48)

⟹𝑅𝐼= 1+𝑟𝑝1−𝑟𝑝

𝐸𝑞𝑢 .4


Summary of frequency-domain (transmission) RI calculation of (demonstrated with glass slides)

Fig 1: Raw TD waveform of silica.

• Stock software supplied with the TPS-3000 includes a routine fast Fourier transformation.

• The FD method translates the time-domain functions of the raw transmission waveform with Equ 1.

0 1 2 3 41.0

1.5

2.0

Stable THz region

Frequency, THz

RI

305 310 315 320 325-4

-2

0

2

4

6

8

Silica

Optical Delay, ps

THz E

-Fie

ld ×

103,

a.u

.

FFT

𝑅𝐼 (~𝑣 )=1+¿

𝐹𝐹𝑇 :𝐸 (𝑧 ,𝜔 )= 12𝜋 ∫

−∞

∞

𝐸 ( 𝑧 ,𝑡 )𝑒−𝑖 𝜔𝑡𝜕𝜏 𝐸𝑞𝑢 .1

• The imaginary component of the complex number supplies transmittance phase information () and is used to produce a RI spectra with the use of Equ. 2 and then plotted (Fig 2), whereby a stable region of RI values are used in our studies.

Fig 2: FD RI spectra of silica.


Roller Compaction

The three major units of a typical roller compactor :A feeding system (1-4) : powder conveyance to the compaction area between the rolls.A compaction unit (5) : powder is consolidated between 2 rollers forming ribbons by force.A size reduction unit (6) for milling the ribbons to the desired particle size.

Importance of Process Parameters: Force and Roll Gap• Force is the most important

parameter in the dry granulation process as it defines density and the strength if the ribbon, along-side,

• The Roll Gap (as the secondary most critical PP). The RPM is a tertiary setting and chiefly influences ribbon throughput

• At a given force, the powder will be compacted to a pre-defined ribbon thickness depending on the amount of powder conveyed to the rolls.

A typical horizontal and diagonal feed RC unit.


RC Process Control

A Gerteis Mini-PolyGran GUI

User defined GAP (2nd greatest PP influence of ribbon quality). The adjacent white-box reports the current parameter.

User defined Roll-speed (3nd greatest PP influence of ribbon quality).

User defined FORCE (1st greatest PP influence of RC quality): Set at 5 kN/cm, force-inducers monitor resistive strain along with the defined gap. Achieved

Dynamic control of feeding system. Material feed of augers at rate to force the rolls apart to max GAP and met defined FORCE

Feed rate controlled

GAP: USER DETERMINED

FORCE: USER DETERMINED

RPM: USER DETERMINED

Feed-back: Process parameters monitored


Road map of project

• FDT THz RI SF%.∝• RTS tested off-line.• Thickness a pre-requisite.

Ribbons Glass slides

TabletsTHz Uses

OutputRI values agree within 5% of FD

literature valuesTD methods validated for glass slides

FD RI values known from literature RI depends on chemistry

OEM standards : Precise thickness & homogeneousEvaluate TD methods for RI determination

(i) OD in transmission mode(ii) OD in reflection mode

(iii) Amplitude coefficient in reflection modeCompare TD RI vs FD RI (literature)

Unknown RI : Measure RI by FD methodRI depends on solid fraction

Precise thickness & quasi-homogeneousSolid fraction f (depth into tablet)

Evaluate TD methods for RI determination (i) OD in transmission mode

(ii) OD in reflection mode(iii) Amplitude coefficient in reflection mode

Compare TD RI vs FD RI (measured)

OutputRI values agree within 5% of FD

literature valuesTD methods validated for

tablets

Mechanical strength prediction:Measure RI by FD method and RTSRI depends on solid fraction and is

∝ to thickness Evaluate FD method for non-destructive RTS determination

(i) Tablets with fixed mass compressed at greater forces(ii) Tablets produced with equal compactionforces will constant mass. Compare FD RI vs RTS

OutputRI can est. RTS when fill-weight remains constant. Less success

with others: agglomeration forces?

Unknown: RI’s, effect of machine (system/user PP’s) and formn RC’s: Gerteis (smooth rolls), AlexanderWerk (knurled).RI depends on SF & character of ribbon.

Evaluate TD methods for RI determination/thkn (i) OD in transmission mode(ii) OD in reflection mode(iii) Amplitude coefficient in reflection modeCompare TD RI vs FD RI (FDT)


Identification of ribbon density profiles was illustrated by x-ray diffraction (atomic cloud density) [Simon and Guigon, 2001]

In this case, it can be see that the density map is a consequence of the RC design

Relative quantification

Example of a non-homogeneous ribbon


Accurate RI and Thickness prediction (TD): Glasses

Glass Specifications Silica Pyrex BK7 UnitsLiterature RI 1.950 2.100 2.500 n

Actual Thickness 1.08 1.73 1.03 mmOptical Delay Analysis: RI (for Signal Delay)

Δ OD 3.433 6.329 5.162 psRI as function of SD 1.953 2.097 2.556 n

Difference 0.003 -0.003 0.032 nMean & Error from Mean Lit RI 0.151 -0.155 1.289 %

Optical Delay Analysis: RI (for Internal Delay)Δ OD 14.032 23.916 17.21 ps

RI as function of internal echoes 1.948 2.072 2.505 n

Difference -0.002 -0.028 0.054 %

Mean Percentage Error from Lit RI -0.126 -1.323 2.167 %Reflection method

Amplitude Coefficient 0.323 0.359 0.441 rpReflection RI 1.953 2.119 2.580 n

Difference 0.003 0.019 0.080 nMean Percentage Error from Lit RI 0.18 0.90 3.21 %

Thickness Prediction (Predicted reflectance RI OD methods)Predicted thickness 1.06 1.64 1.03 mm

Percentage Thkn error -1.34 -3.82 -0.69 %

Material RI Thickness Prediction

Limitations of methods:• Substrate must lie in precise positioning to the

antennae.Transmission• Thkn or RI must be known.• Fabry-Pérot events are not always present for ID

measure.Reflection• * Simplification of Fresnel coefficient reduces RI

accuracy by < 1%.

• Lit. error bars, n = 3, broad THz frequency limits, calliper degree of sensitivity.• Combined OD error bars, n = 3, calliper degree of sensitivity.• TPI/Reflection error bars, n=3 calliper degree of sensitivity, • method constraints.

Silica Pyrex BK71.60

1.80

2.00

2.20

2.40

2.60

2.80

Literature

Combined SD & ID TDT thkᶯ results

TPI/Reflection

TH

z R

I

Glass slides


FD measurements of RI of tablets 37 tablets of MCC were prepared (with variable fill weights and compaction force) and

analysed with FD transmission spectroscopy to establish RI as a function of SF/density A linear (line of best fit) extrapolation to a RI of <1, crossing the density axis at ~ 0.06 Given that the RMSE for density is 0.005 g/cm3 then measurement precision alone may not

explain the low value for the intercept. The alternative might be a non-linear relationship For a tablet of bulk density 1.00 g/cm3 the measurement precision is 0.4%. In terms used by

the ICH Q2 guideline (Directive 75/318/EEC) this represents an LOD of 1.3%.

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6

52% 57% 62% 67% 72%

1.0

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

2.0

f(x) = NaN x + NaN

Fixed Force (420kg)/Var. WeightFixed Force (320kg)/Var. WeightFixed Weight (200mg)/Var. ForceLinear (Fixed Weight (200mg)/Var. Force)

Bulk Density, g/cm3

RI,

ñ

@ 0

.3 -

1.5

TH

z

Solid Fraction, %

RMSE for density is 0.005 g/cm3

0.06 g/cm3.

Tablets


Compare TD RI vs FD RI (measured)

10 pharmaceutical tablets of Avicel with a constant volume (thus Thkn) & variable densities were analysed.

The mean of FDT RI’s are calculated between 0.3 - 1.5 THz and transmission optical-delay & amplitude reflection results reported.

FFT is considered as the ‘gold-standard’ for RI’s are true at specific EMR frequencies.

0.00 0.20 0.40 0.60 0.801.001.051.101.151.201.251.301.351.401.451.50

f(x) = 0.477104774102654 x + 1R² = 0.999418973097159

f(x) = 0.559155147620015 x + 1R² = 0.999970934292717

f(x) = NaN x + 1R² = 0

FFT RILin-ear (FFT RI)OD RILin-ear (OD RI)rp RILinear (rp RI)

Density, g/cm3TH

z RI

* Error bars are the result of repeat experiments (n=3), the callipers degree of sensitivity. For FFT, broad RI ranges of are reported because of narrow region of stable frequencies

305 310 315 320 325 330 335 340-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

-0.04

0.02

Breadth

ρ = 0.59 g/cm³ρ = 0.66 g/cm³ρ = 0.69 g/cm³ρ = 0.72 g/cm³

Optical-delay, ps

THz

E-Fi

eld

(×10

3), a

.u.

THz

E-Fi

eld

(×10

³), a

.u.

0.5 0.6 0.7 0.8 0.9 1.00.5

0.7

0.9

1.1

1.3

1.5

1.7

0.020

0.021

0.022

0.023

0.024

0.025

0.026

R² = 0.934672001370688

R² = 0.987654477416376

Bulk density, g/cm3

1st m

ax E

-fiel

d pe

ak (×

10³ )

, au

2nd

max

E-fi

eld

peak

(×10

³ ), a

.u.

TD Transmission time-delay

Magnified 2nd peak

E-Fieldmax (t) magnitudes• Breadth and

detection of Emax

more accurate than 2nd EMax .

• At greater density, detection of 2nd EMax(t) is harder to distinguish.

0.00

0.05

0.10

0.15

0.20

0.25

First max. Breadth

ρ = 0.93 g/cm³ρ = 0.89 g/cm³ρ = 0.86 g/cm³ρ = 0.79 g/cm³ρ = 0.79 g/cm³ρ = 0.76 g/cm³ρ = 0.72 g/cm³ρ = 0.69 g/cm³ρ = 0.66 g/cm³ρ = 0.59 g/cm³

Optical Delay, ps

Am

plit

ude,

a.u

.

Tablets

TD Reflection


Evaluate FD method for non-destructive RTS determination

RI correlation was first demonstrated to a degree >0.99 Four batches comprised of 2 set off MCC:

• Set 1 with 2 fill weights and variable compaction force.• Set 2 with 2 compaction-forces and variable fill weights

Analysed with FD transmission spectroscopy and then diametrically crushed, giving RTS. An apparent linear line of best fit (see Fig ‘a’ and ‘b’) can be drawn over both tablet batches’ while both

sets converge and cross over with increased density. Given that the 200 & 295 mg set have a greater R2, the cross-over point indicates that the fill-weight

volume influences the resistive consolidation mechanisms produced under different duress. Set 2 highlight that particle-particle binding mechanisms are different again a function of particle volume and temporary (i.e. elastic) and permanent forces.

As a further use of THz technology, the RTS of tablets of comparatively equal FW’s are more reliably indicatory of RI.

RTS

0.80 0.85 0.90 0.95 1.00 1.05 1.10 1.15 1.20

0.80 0.90 1.00 1.10 1.20

0.00

0.40

0.80

1.20

1.60

2.00

2.40

2.80

3.20

0.60

1.00

1.40

1.80

2.20

2.60

3.00

R² = 0R² = 0

200 mg tablets

(a) SET 1 Density, g/cm3

RTS

, M

Pa

0.8 1.0

0.8 0.9 1.0 1.1

0.4

0.9

1.4

1.9

2.4

2.9

0.4

0.9

1.4

1.9

2.4

2.9R² = 0R² = 0

320 kg tablets

(b) SET 2 Density, g/cm3

RTS

, M

Pa

F.W.C.F.


Multi-variant sets of RC ribbons

To elucidate varying RI lateral and longitudinal density to the key process and machine parameters.

State Limitations.Produced Ribbons Composition (w/w%) Equipment set-up CharacterAlexandwerk WP-120

15 RC’s10 Wafers

Avicel® PH-102 (78.6 %) Anhydrous lactose (19.4 %) Croscarmellose Na (1.5%) Mg stearate (0.25%)

n =10 Variable: Compaction-Force.- Compressed at 4.79 – 6.79 kN/cm.-Roll-gap: 2.2 mm - Knurled roller-wheel. - Knurled wafer press.

Ribbon SF’s / Mean Thkn: 63 % / 2.78 mm 76 % / 2.68 mm 83 % / 2.82 mm

Wafer SF’s / Thkn

63 % / 2.32 mm 83 % / 2.27 mm 90 % / 2.28 mm

Gerteis Micro-Pactor

16 samples Vivapur 102 (78.0 %) Anhydrous lactose (18.25 %) Croscarmellose Na (3.0 %) SiO2: Supernat 160 (½ %) Mg stearate (¼ %)

Smooth roller-wheel.

Roller-speed: 3 mm.

Roller-force: 1/5/10/15 kN/cmRoller-gap: 1/2/3/4 mm.

Roller-force: 1/5/10/15 kN/cmRoller-gap: 2/4 mm.

8 samples • Avicel® PH-101 (100 %)

Ribbons


Limitation # 1: Problems with knurled wafer/ribbons

Knurled wafers and ribbons prevent either an accurate RI or thickness to be predicted when imaged.

• (a) Reflectance waveform acquired from both front and rear surfaces: One face knurled.• RI can be taken of smooth face, but then

Thkn inaccurate.

(b) Probing from knurled face is unreliable depending on placement. • Knurled surfaces cause unpredictable

signal propagation causing ripples.

Ribbons


Limitation # 2: Problems with non-planar ribbons

For accurate prediction of RI’s the intensity of the probe beam is contrasted to a flat mirror, which is then removed and focused (z-dimension) on initial position before scanning

Multiple lateral/longitudinal scans of curved ribbons give fluctuating amplitudes when moved from the fixed reference point.

• A ribbon with a planar lateral character.• Often the product of using smooth roll-wheels.

• A ribbon with a curved lateral character.• The majority of curved ribbons are produced

with knurled rolls.

Ribbons

?

: reliable RI = reliable Thkn

: specular/flat interception


Effect of Roll Force and Thkn: Examples of Blend 1: 1 mm thick ribbons

Composition 1 (w/w%) Vivapur 102 (78.0 %) Anhydrous lactose (18.25 %) Croscarmellose sodium (3.0 %) SiO2: Supernat 160 (½ %) Magnesium stearate (¼ %)Smooth rolls/3 RPM

Variables:Force 5/10/15 kN/cm

Roll Gap 1/2/3/4 mm

Composition 2 (w/w%) Avicel PH-101 (100%)

Variables: Force 5/10/15 kN/cm

Roll Gap 1/2 mm

40 reflection scans per ribbon were made.

(a) Histogram displaying the distribution of the all the ribbons (points analysed/ribbon = 40),

Individual contour images are shown:(b) 05 kN/cm(c) 10 kN/cm(d) 15 kN/cm(e-g) Mean lateral I distributions are plotted, with error bars for the minimum to maximum RI’s along the ribbons’ length.

Ribbons


Results of the effects of Roll Force and Thickness of Composition 1

Composition 1 (w/w%) Vivapur 102 (78.0 %) Anhydrous lactose (18.25 %) Croscarmellose sodium (3.0 %) SiO2: Supernat 160 (½ %) Magnesium stearate (¼ %)

Smooth rolls/3 RPMN = 18

Variables:Compaction Force 5/10/15 kN

Roll Gap 1/2/3/4 mm

• Linear relation at lower forces (i.e. 5 to ~ 7.5 kN/cm)• Material consolidation lessens as True densities approach.• Broader ribbons report maximum SF’s at lower force.• Agglomeration of thin ribbons remains curved over great

forces. This suggests consolidation processes (i.e. particle rearrangement, interlocking, brittle fracture.

* The error bars show RI variance longitudinally over the 18 ribbons (points analysed/ribbon = 40).

Ribbons

Visually linear

1mm

4mm


Results of the effects of Roll Force and Thickness of Composition 2

Composition 2 (w/w%) Avicel PH-101 (100%) n = 6

Variables: Compaction Force 5/10/15 kN

Roll Gap 1/2 mm

* The error bars show RI variance longitudinally over the 6 ribbons (points analysed/ribbon = 40).

• Linear relation at lower forces (i.e. 5 to ~ 8 kN/cm).• Although fewer points as previous slide, the deformation

character of MCC alone (leading to similar RI’s) is less prone to a broad number of consolidation processes in approaching an apparent SF indicative of MCC’s true densities

Ribbons

Date post:	13-Aug-2015
Category:	Documents
Upload:	l-alex-wall
View:	108 times
Download:	1 times

2015-03-26 Thesis Overview

Documents