MIC

ROCE TABLETING →
DIRECT COMPRESSION →
CO-PROCESSED LACTOSE

LAC
Technical brochure
MicroceLac® 100
MEGGLE’s co-processed lactose grades
for direct compression: MicroceLac® 100

General information Product description

Direct compression (DC) tablet manufacture is a popular choice Alpha-lactose monohydrate and microcrystalline cellulose are
because it provides the least complex, most cost effective pro- functional excipients used in oral solid dosage forms. Both are
cess to produce tablets compared to other tablet manufacturing naturally derived and commonly used in the pharmaceutical
approaches. Manufacturers can blend APIs with excipients and ­industry, either individually or in combination. To develop syner-
compress, making dosage forms simple to produce [1, 2]. gistic functional performance, such as increased compactability
and powder flow, alpha-lactose monohydrate and microcrystal-
DC technology and the use of modern tableting equipment line cellulose were co-spray-dried, creating a monoparticulate
require that excipients and APIs form a compactable mixture with system having two compaction mechanisms, brittle fracture and
excellent flowability and low particle segregation tendency [3]. plastic deformation, within individual particles. MicroceLac® 100
provides the flow and compaction properties desired for direct
In the pharmaceutical industry, lactose is one of the most compression tableting. MicroceLac® 100 comprises 75 % alpha-­
commonly used excipients; however, like many other excipients, lactose monohydrate and 25 % microcrystalline cellulose (MCC),
­lactose may not be suitable for direct compression without both maintaining their individual chemical identities.
modification due to insufficient powder flow or/and compaction
properties (figure 1).

Lactose performance
Flowability/compressability
Good
WG DC
Powder flow

WG DG
Low Powder compressability High

Figure 1: Powder blend compressability and flowability requirements

for various tableting technologies (DC is direct compression, WG is
wet granulation, DG is dry granulation) [3].

2 MEGGLE | Co-processed lactose MicroceLac® 100 | 2023-07

Regulatory & quality information Application

The raw materials used to produce MicroceLac® 100, alpha-­lactose MicroceLac® 100 is designed for direct compression and may be
monohydrate and microcrystalline cellulose, comply with Ph. Eur., applied to other formulation development approaches such as
USP-NF, and JP monograph requirements. Since no chemical dry granulation and capsule filling. In comparison to a physical
modifications result during co-processing and i­ndividual chemical blend of the individual components, MicroceLac® 100 provides
identities are maintained, MicroceLac® 100 can be considered enhanced compaction and superior flowability. These attributes
as a physical blend of alpha-lactose mono­hydrate and micro- improve blending and mitigate API content variability typical of
crystalline cellulose [4]. simple powder blends. MicroceLac® 100’s superior blending char-
acteristics make it ideal for low-dose formulations where API
A MicroceLac® 100 drug master file (DMF) is available during content uniformity is critical. Excellent compaction properties
FDA (Food and Drug Administration) drug product submission help increase tablet hardness, making it well-suited for high-
review and approval. Specifications and regulatory documents dose formulations as well. MicroceLac® 100 maximizes formula-
can be downloaded from www.meggle-pharma.com. tion development flexibility.

Our pharma-dedicated production facility in Wasserburg,

­Germany, is certified according to DIN ISO 9001:2015 and has
implemented GMP according to the Joint IPEC-PQG (Good — Direct compression
­Manufacturing Practices Guide for Pharmaceutical Excipients) — Dry granulation (Roller compaction, slugging)
and USP-NF General Chapter <1078> GOOD MANUFACTURING — Capsule filling
PRACTICES FOR BULK PHARMACEUTICAL EXCIPIENTS.
­MEGGLE has been an EXCiPACT™-certified excipient manu­
facturer and supplier since 2014.

The Wasserburg facility demonstrates MEGGLE’s complete

BENEFITS
­lactose production capability range, including sieving, milling,
agglomeration, spray-drying, and co-processing. Additionally
MEGGLE is a member of IPEC (International Pharmaceutical MicroceLac® 100
­Excipients Council).
— Excellent compactability and flowability
MEGGLE invests considerably in the sustainability of raw material — Ideal for poorly compactable APIs, e.g. herbal extracts
sourcing, production standards, and efficiency. We are actively — Ideal tablet surface for straight forward and economical
engaged in environmental protection. In order to guarantee the coating
quality of our products, our commitment and adherence to estab- — High adherence capacity prevents segregation and
lished pharmaceutical standards remains is our highest priority. subsequently improves content uniformity

MEGGLE | Co-processed lactose MicroceLac® 100 | 2023-07 3

Particle size distribution (PSD)

Figure 2 shows typical laser diffraction particle size distribution Figure 3 depicts the specified PSD range and typical average
data for MicroceLac® 100. MicroceLac® 100 possesses a narrow values by air-jet sieving. These parameters are constantly moni-
PSD that supports homogenous powder blend preparation, a tored through in-process control (IPC) testing and are part of
­requirement for achieving good tablet quality. the MicroceLac® 100 particle size distribution specification.

Typical particle size distribution (Laser diffraction) Typical particle size distribution (Laser diffraction)
MicroceLac® 100 – co-processed grade, cumulative PSD MicroceLac® 100 – co-processed grade, distribution density
Cumulative distribution Q3(x)/% Distribution density q3lg(x)
100 1.6
90 1.4
80
1.2
70
60 1.0
50 0.8
40 0.6
30
0.4
20
10 0.2
0 0
1 10 100 1000 1 10 100 1000
Particle size (µm) Particle size (µm)

Figure 2: Typical cumulative PSD and distribution density of MEGGLE’s MicroceLac® 100. Analyzed by Sympatec®/Helos & Rodos particle size analyzer.

Sieve data – co-processed lactose

Lactose type MicroceLac® 100
specified/typical
Particle size distribution < 32 µm NMT 15 %/ 7 %
Method: Air-jet sieving < 160 µm 45–70 %/59 %
< 250 µm NLT 90 %/95 %

Figure 3: Specified PSDs for MicroceLac® 100 by air-jet sieve in bold letters. Typical values obtained from
a permanent in-process control are shown for orientation.

4 MEGGLE | Co-processed lactose MicroceLac® 100 | 2023-07

Batch-to-batch consistency Isotherms

Batch-to-batch consistency for all lactose products can be MicroceLac® 100 exhibits moderate moisture uptake while
attributed to MEGGLE’s long history and experience in lactose exposed to high relative humidity conditions due to the MCC
manufacture, and broad technical expertise. Constant in-process ­influence on observed equilibrium moisture content (figure 5).
and final product testing ensures consistency and quality (figure 4).

Batch-to-batch consistency – particle size distribution – co-processed lactose Sorption isotherm (Dynamic vapor sorption at 20 °C)
MicroceLac® 100 MicroceLac® 100
Passing through 100 Weight change (%)
sieve (%) 5.0
80 4.5
4.0
60 3.5
3.0
40 2.5
2.0
20 1.5
1.0
0 0.5
Particle size (µm) < 32 < 160 < 250 0.0
Specified NMT 15 % 45 – 70 % NLT 90 % 0 20 40 60 80 100
Mean IPC value (%) 7.0 58.8 95.2 Relative humidity (%)
SD (%) 1.2 2.2 0.8 Sorption Desorption
Particle size distribution batch-to-batch consistency of MicroceLac® 100 by air-jet-sieving.
Figure 4: MicroceLac®
Data obtained from a100 particle size
permanent distribution batch-to-batch
in-process-control consistency
(IPC) of subsequent by air-jet
batches oversieve
a analysis. Figure 5: Sorption-desorption isotherms (20 °C) of MicroceLac® 100. Analysis performed by SPSx-1µ
Data
timeobtained
period offrom a permanent in-process control (IPC) of subsequent batches over 12 months.
12 months. moisture sorption test system.

Scanning electron micrograph (SEM)

MicroceLac® 100 is nearly spherical in shape due to the co-

spray-drying manufacturing process. MicroceLac® 100’s overall
morphology reduces blend segregation and improves finished
dosage form content uniformity (figure 6).
800 µm

Figure 6: SEM image of MEGGLE’s MicroceLac® 100 by ZEISS Ultra

MicroceLac® 100
55 FESEM (U = 5 kV; Au/Pd sputtered).

MEGGLE | Co-processed lactose MicroceLac® 100 | 2023-07 5

Functional related characteristics

Powder flow Flowability

In assessing powder flow using a FlowRatex® apparatus, Co-processed MicroceLac® 100 vs. physical blend
­MicroceLac® 100 exhibited superior flowability compared Volume flow rate (ml/s)
to a physical blend, made up of spray-dried lactose and micro- 25
crystalline cellulose. The simple blend of individual ingredients 20
showed greater flow variation compared to MicroceLac® 100 15
(figure 7). MicroceLac® 100 also possessed lower flowability 10
­index (MicroceLac® 100 = 2 mm, physical blend = 9 mm),
5
indi­cating superior flowability (figure 8).
0
Flowability can also be described by the Hausner ratio, Carr’s 0 1 3 5 7 9 11 13
­index, or angle of repose. A Hausner ratio below 1.25 or Carr’s Aperture (mm)
index below 20 indicates that powders are freely flowing. MicroceLac® 100 FlowLac® 90 + MCC
Angle of repose describes “good flowability” between 31– 35°,
Figure 7: Volume flow rate (ml/s) as a function of aperture size (mm diameter) for MicroceLac® 100 and
and in general, worsens with steeper angles. Figure 9 shows a comparable physical blend analyzed by a FlowRatex®.
typical flowability indices for MicroceLac® 100, indicating excel-
lent ­flowability.

Flowability Flowability
Co-processed MicroceLac® 100 vs. physical blend MicroceLac® 100 – co-processed lactose
Flowability index (mm) Angle of Density bulk Density Hausner ratio Carr’s index
25 ­repose (°) (g/l) tapped (g/l) (%)
MicroceLac® 100 34 460 580 1.26 21
20 Poor flow
Figure 9: Typical powder technological values for MicroceLac® 100. Pharmacopoeial methods were used.

15 Moderate flow

10 Good flow

5 Very good flow

Excellent flow
0
Adherence capacity
MicroceLac® 100 FlowLac® 90 + MCC Content uniformity – physical blend: lactose and microcrystalline cellulose
Content glibenclamide (%)
Figure 8: Flowability index of MicroceLac® 100 and its corresponding physical blend. 12
Smaller values indicate better flowability.
9

6
Adherence capacity 3
Due to its particle morphology, MicroceLac® 100’s excellent flow
properties create the shear necessary to disperse API during 0
low-dose blending operations thereby improving content uni­ 0 10 20 30
formity. Studies have shown that a homogenous powder blend Blending time (min)
comprising 5 % glibenclamide can be achieved using Sample 1 Sample 2 Sample 3
­MicroceLac® 100 (figure 10b) compared to the use of a simple
physical blend (figure 10a), [5]. Adherence capacity
Content uniformity – MicroceLac® 100
Content glibenclamide (%)
12

0
0 10 20 30
Figures 10a and 10b: Content uniformity of a powder blend
Blending time (min)
­comprising 5 % glibenclamide and either MicroceLac® 100
or the individual components, lactose and MCC [5]. Sample 1 Sample 2 Sample 3

6 MEGGLE | Co-processed lactose MicroceLac® 100 | 2023-07

 Compactibility Compactibility and friability
Co-processed MicroceLac® 100 vs. physical blend Tablet hardness can be increased by combining lactose and
Tablet hardness (N) ­microcrystalline cellulose. Results have shown that
400 ­MicroceLac® 100’s compactibility is superior to a comparable
physical blend of the individual components in the same ratio
300 (figure 11). Due to excellent compactibility, low friability (< 1 %) is
given (figure 12), eliminating the need for a protective coating.
200

100

0
0 10 20 30 40
Compaction force (kN) Figure 11: Tablet hardness profile for MicroceLac® 100 compared to a
physical blend of the individual components and Tablettose® 80
Tablet press: IMA Styl’One 105ML, Tablets: Ø 11.3 mm, 500 mg
(granulated lactose). Tablets were produced using a tablet press:
MicroceLac® 100 FlowLac® 90 + MCC
IMA Styl’One fitted with 11.3 mm punches. Average tablet weight
Tablettose® 80 + MCC Tablettose® 80 was targeted at 500 mg.

Friability
Co-processed MicroceLac® 100 vs. physical blend
Friability (%)
3

0
0 1 2 3 4
Tensile strength (N/mm 2)
Figure 12: Friability for tablets produced either with
MicroceLac® 100 Tablettose® 80 + MCC MicroceLac® 100 or its corresponding blend.

Packaging and shelf life Packaging and shelf life

MicroceLac® 100 Packaging material complies with Regulation (EC) No. 1935/2004
Size Material Shelf life and 21 CFR 174, 175, 176, 177 and 178. Stability tests have been
MicroceLac® 100 20 kg Paper bag with PE-EVOH-PE inliner 18 Months performed according to ICH guidelines and an ongoing stability
program is implemented. Figure 13 provides an overview about
Figure 13: Packaging and shelf life of MEGGLE’s MicroceLac® 100.
packaging size and material, and product shelf life.

MEGGLE | Co-processed lactose MicroceLac® 100 | 2023-07 7

Literature

[1] M eeus, L. (2011). Direct Compression versus Granulation.

Pharmaceutical Technology, 23(3).
[2] Kristensen, H. G., Schaefer, T. (1987). Granulation: A Review
on Pharmaceutical Wet-Granulation. Drug Development and
Industrial Pharmacy, 13(4–5), 803–872.
[3] Mîinea, L. A., Mehta, R., Kallam, M., Farina, J. A., Deorkar, N.
(2011). Evaluation and Characteristics of a New Direct Com-
pression Performance Excipient, 35(3).
[4] Guideline on Excipients in the Dossier for Application for
Marketing Authorization of a Medicinal Product. EMEA/
CHMP/QWP/396951/2006.
[5] By courtesy of Prof. Sunada, Meijo University, Nagoya.

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use, application, and compliance of this product with regard to any national, regional, or local laws
83512 Wasserburg [email protected]
and/or regulations is the sole responsibility of the user, and MEGGLE makes no representation with
Germany www.meggle-excipients.com regards to same. Nothing herein shall be construed as a recommendation or license to use the product
or any information that conflicts with any patent or intellectual property of MEGGLE or others and any
such determination of use is the sole responsibility of the user. © MEGGLE EN 2023-07 Sai